\r\n\tIn this book the authors will provide complete introduction of Polymers chemistry. The book is mainly divided into three parts. The readers will learn about the basic introduction of general polymer chemistry in the first part of the book. \r\n\tThe second part of the book starts with a chapter which includes kinetics of polymerization. Polymer weight determination, molecular weight distribution curve and determination of glass transition temperature. The final part of the book deals polymer degradation which includes types of degradation. The chapters of the present book consist of both tutorial and highly advanced material.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"58184",title:"Benign Tumors of Temporomandibular Joint",doi:"10.5772/intechopen.72302",slug:"benign-tumors-of-temporomandibular-joint",body:'\n
\n
1. Introduction
\n
Primary neoplasms of the bones are rare, amounting to only 0.2% of the overall human tumor. Primary neoplasms originating in the temporomandibular joint (TMJ) are extremely rare. Their clinical manifestations are usually related to the temporomandibular dysfunction (TMD) and include pre-auricular swelling, pain, trismus, deviation of mandibular movement and malocclusion. Such symptoms should not be neglected and advanced imaging methods should be used with the thought that it may be neoplasia. Also the clinical symptoms and radiological appearance of many tumors are similar. Therefore, the differential diagnosis must be made carefully [1].
\n
Temporomandibular joint consists of bone structures and soft tissues such as temporal bone, mandibular condyle, articular disc, articular capsule and ligaments. The tumors that will be formed in this region will also develop from bone and soft tissue origin.
\n
The most common TMJ-specific benign tumors are classified after a brief literature review. Our classification also includes the osteoma of the TMJ, other than World Health Organization’s (WHO) classification of soft tissue and bone tumors [2]. This benign tumor also included in the classification because of its higher frequency in the literature (\nTable 1\n).
\n\nTable 1\n represents benign TMJ tumors. These tumors are classified under two section.
\n
\n
\n
2. Cartilage tumors
\n
Tumors producing a chondroid matrix will be described in this group. Many benign cartilage tumors are asymptomatic. Radiographic findings are critical to diagnosis of cartilaginous tumors.
\n
\n
2.1. Osteochondroma
\n
Osteochondroma is a common slow-growing tumor that cartilage-capped bony projection arising from the outside surface of bone containing a marrow cavity that is continuous with that of the underlying bone appears close to the growth plate at the end of long bones [3]. In very few cases of temporomandibular joint, osteochondroma have been reported [4]. Osteochondroma is usually located at the medial surface of mandibular condyle [5]. The average age of occurrence is 16.5 and males are affected 3 times as often as females [6].
\n
The most common clinical symptoms are malocclusion, with unilateral posterior open bite on the affected side and a crossbite on the contralateral side, and progressive facial asymmetry, limited and often painful mandibular movements and clicking [7, 8].
\n
The reason for osteochondroma is uncertain, but traumatic, developmental, neoplastic and reparative occasions have been considered as possible factors [6, 9]. The most commonly accepted view is a metaplastic change of the periosteum and/or the osteochondral layer in the condyle, leading to the production of cartilage, which subsequently ossifies [8]. Complications of OC are osseous deformity, fracture, vascular compromise, bursa generation and malignant transformation [6]. CT can provide excellent anatomy of the lesion and demonstrate calcification in the cartilage cap whereas MRI confirms the diagnosis by demonstrating the cartilaginous cap [4].
\n
The differential diagnosis of benign neoplasms known to involve the mandibular condyle includes osteoma, osteoblastoma, chondroma, chondroblastoma and osteochondroma. Osteomas are benign tumors that consist primarily of mature, compact, cancellous bone [9]. Chondromas consist of well-defined lobules of mature hyaline cartilage that may contain areas of calcification. Chondroblastomas consist of a proliferation of immature cartilage cells, with focal production of a variably differentiated cartilaginous matrix [10]. Osteochondroma is presumed to arise from herniation of cartilage through the epiphyseal plate in the formative years. Radiographically, the lesion is easily differentiated from chondroma because it is most frequently an extraneous appendage, rather than a rarefaction within the normal jaw confines, and is more radiopaque, which represents its true ossification [11].
\n
Osteochondromas can be treated by total condylectomy or local resection of the lesion and condylar replacement if the tumor involves the mandibular condyle. On the other hand, if the tumor affects limited part of the condylar surface, preservation of the remaining part of the condyle and reshaping can be done [6, 12].
\n
In the case of an osteochondroma of the author of this chapter, Dr Karasu, the tumor was removed under general anesthesia. On a panoramic radiograph, a well-defined, bone-like, radiopaque mass was seen in the left condylar head (\nFigure 1\n). Axial and coronal computed tomographic (CT) scans revealed an opaque mass around the mandibular condyle (\nFigures 2\n and \n3\n). The patient’s three-dimensional CT image showed a large mass in the anteromedial region of the left condyle (\nFigure 4\n). The tumor was excised under general anesthesia. The upper and lower compartments of the temporomandibular joint were accessed through an auriculotemporal approach. The surgical field was expanded with retraction along the masseter muscle downward. The disc, which adhered to the lesion at the anterior aspect of the condyle, was resected. The tumor was resected en bloc. The lesion could be easily separated from the surrounding tissues (\nFigure 5\n). Histologically, it was noted that the nodular mass was covered with a proliferative cap of cartilage with underlying zones of cancellous bone and irregular calcified cartilage. The osteocytes and chondrocytes were individually housed in a lacuna with a single nucleus (\nFigure 6\n). Sixteen-year follow-up assessments revealed satisfactory function and occlusion. There was no evidence of recurrence [11].
\n
Figure 1.
Panoramic radiograph, showing a bone-like, radiopaque mass in the left condylar head.
\n
Figure 2.
Axial CT scan, showing a well-defined, opaque mass.
\n
Figure 3.
Coronal CT scan, showing localization of the osteochondroma.
\n
Figure 4.
Three-dimensional CT view of the osteochondroma.
\n
Figure 5.
Mass resected from the left condyle.
\n
Figure 6.
Histopathological aspect of the osteochondroma. The cancellous bone is surfaced by a cap of hyaline cartilage (HC). A zone of endochondral ossification (EO) appears between the cartilaginous cap and underlying cancellous bone (hematoxylin and eosin; magnification, 200).
\n
\n
\n
2.2. Chondroma
\n
Chondroma is a rare, benign tumor of mature hyaline cartilage of mesenchymal origin [13]. Chondromas, are common in the small bones of the hands and feet, but are extremely rare in the TMJ area [14, 15]. Chondromas are classified into three types as (a) enchondroma that arises from medullary cavity, (b) juxtacortical that originate adjacent to the periosteum below the cortical face and (c) extra-skeletal that can be seen in the tongue and buccal mucosa [16, 17]. Chondromas are equally seen in men and women and most patients are 30–40 years old [14].
\n
Chondromas are generally asymptomatic. Its signs and symptoms can mimic those of patients with more common disorders of facial asymmetry or dysfunction of the temporomandibular joint as clicking, limited mouth opening and deviation [18].
\n
Radiographically, chondromas are irregular radiolucent or mottled region of the bone. There may be some calcification foci ranging from powder like to dense aggregates [19].
\n
The differential diagnosis for bony or cartilaginous hyperplastic lesion of the temporomandibular joint may include condylar hyperplasia, osteochondroma, osteoma, chondroma, osteoblastoma, fibrous dysplasia, ossifying fibroma (OF), chondromyxoid fibromas, synovial chondromatosis, chondroblastoma, chondrosarcoma and osteosarcoma [20, 21].
\n
Chondromas can be treated as low-grade chondrosarcomas by surgical treatment of mandibular condyle to avoid recurrence [13].
\n
\n
\n
2.3. Chondroblastoma
\n
Chondroblastoma is a rare benign, cartilaginous, destructive tumor derived from immature cartilage cells which occurs infrequently in the head and neck area [22, 23]. Most chondroblastoma cases arise in the epiphysis of long bones such as distal femur, proximal tibia and proximal humerus [24]. It is more common in women [25].
\n
Chondroblastoma shows similar clinical symptoms associated with temporomandibular disorders such as sound in the joint, decreased range of motion, swelling, pain, trismus and changing occlusion. If chondroblastoma occurs at the temporal bone, additional symptoms such as otalgia, paresthesia, hearing loss, ear noise and facial nerve weakness may be seen [26].
\n
Computerized imaging (CT) and magnetic resonance imaging (MRI) are the most common diagnostic imaging techniques to identify chondroblastoma. On imaging, round radiolucent lesions with sharp bony edges are found in bone [27].
\n
Differential diagnosis should be done with chondrosarcoma, chondromyxoid fibroma, synovial sarcoma, synovial chondromatosis and aneurysmal bone cyst. Biopsy is necessary for the definite diagnosis [28, 29].
\n
Treatment alternatives are curettage, resection and excision. Chondroblastoma can be treated by conservative curettage when infiltration of bone has not occurred or is limited. Complete excision of the tumor reduces recurrence [30].
\n
In the case of a chondroblastoma of the authors of this chapter, Dr Oncul and Dr Yurttutan, the tumor was removed under general anesthesia. A 35-year-old female patient had complaint of pain and asymmetry. The patient’s three-dimensional CT image showed a large mass in the anteromedial region of the left condyle (\nFigure 7\n). The tumor was resected via a pre-auricular access (\nFigures 8\n and \n9\n), the mass was removed by performing condylectomy (\nFigure 10\n).
\n
Figure 7.
Three-dimensional CT view of the chondroblastoma.
\n
Figure 8.
Intraoperative view of the condyle with the chondroblastoma.
\n
Figure 9.
Intraoperative view after the excision of chondroblastoma.
\n
Figure 10.
Macroscopic view of the pathology.
\n
\n
\n
2.4. Synovial chondromatosis
\n
Synovial chondromatosis (SC) is a rare benign nodular cartilaginous proliferative non-neoplastic lesion arising from the synovial membrane or the fibro-cartilaginous disc of the joints becoming loose bodies within the joint space [3, 31]. The first report of SC of the temporomandibular joint (TMJ) was in 1776 [32].
\n
The etiology of SC is unclear but it is thought to be a trauma history, occlusal disorders, bruxism and degenerative arthritis [33]. SC of TMJ is 2.5 times more common in females, mainly between 30 and 50 years old [34].
\n
SC has three histological stages:
metaplasia found in the synovial membrane without the presence of detached particles.
metaplasia found in the synovial membrane with the presence of detached particles.
presence of detached particles which may vary in size [3].
\n\n
Clinical signs and symptoms of SC is local diffuse pain, pre-auricular swelling, limitation of mandibular movement, joint sounds, tenderness, deviation of mouth opening [35].
\n
Computerized imaging (CT), magnetic resonance imaging (MRI) and orthopantomography are the most common diagnostic imaging techniques. The main findings are widening of the joint space, changes in bone surface of joint and calcified loose bodies [36].
\n
Differential diagnosis should be done with internal derangements, osteoarthritis, osteochondromas, villonodular synovitis, chondroblastoma and focal osteochondritis [37].
\n
Synovectomy with removal of loose body from the joint space is the most preferred procedure. It can be applied in combination with discectomy or condylectomy. No recurrence when loose bodies are removed [38].
\n
\n
\n
\n
3. Osteogenic tumors
\n
Osteogenic tumors are defined as neoplasms that produce an osteoid or bony matrix.
\n
\n
3.1. Osteoma
\n
Osteomas are benign osteogenic tumors involving compact or cancellous bone proliferation and arising from periosteum (peripheral osteoma), endosteum (central osteoma) and even extra-skeletal soft tissue, but they are actually hamartomas that can be seen in membranous bone [39, 40]. Most osteomas of the maxillofacial region occur in the mandible. Peripheral osteomas typically arise at the inferior border of the mandibular body [41, 42]. Only a few cases involving the temporomandibular joint have been reported [43]. Men seem to be more affected than women. The exact cause is unknown, whereas belief in reactive and neoplastic theories maintains [1].
\n
Histologically, compact type osteomas (ivory) consist primarily of dense lamellar bone, and cancellous type osteomas have an abundance of bone marrow [42].
\n
The growth of osteomas occurring in TMJ may result in morphologic and functional disturbances, including facial asymmetry, malocclusion and limited mouth opening [44].
\n
Radiographically, osteoma appears as a well-defined uniform radiopacity or as well-defined radiopacity with evidence of internal trabecular structure. In their centers such masses may exhibit a mixed radiolucent-radiopaque appearance depending on the amount of marrow tissues present [39, 45]. Panoramic radiography, CT, MRI and radionuclide scanning (scintigraphy) have been utilized for imaging of osteomas of the TMJ region [46].
\n
The differential diagnosis is established with exostoses, osteoid osteoma and osteoblastoma [46]. Osteomas of the condyle are lobulated; conversely, hyperplasia results in enlargement of the condyle that retains in its inventive form [47]. Osteoid osteoma and osteoblastoma are frequently painful and grow more rapidly than peripheral osteoma [1].
\n
Large osteomas at TMJ can be treated by condylectomy and tumor resection. No recurrence is reported after surgery [43].
\n
In the case of an osteoma of the author of this chapter, Dr Oncul, the tumor was removed under general anesthesia. A 45-year-old male patient had complaint of habitual luxation which had been present for 5 years and asymmetry (\nFigure 11\n). The tumor was resected via a pre-auricular access (\nFigure 12\n), the mass was removed by performing a condylectomy, preserving the articular meniscus (\nFigure 13\n). Microscopic examination showed a central nidus surrounded by a layer of dense cortical bone. The nidus consisted inconsiderable amount of interstitial connective tissue. No abnormal mitosis or malignancy findings were seen (\nFigure 14\n) [48].
\n
Figure 11.
Preoperative frontal view of the mandibular asymmetry.
\n
Figure 12.
Intraoperative view of the condyle with the osteoma.
\n
Figure 13.
Macroscopic view of the pathology.
\n
Figure 14.
Histopathological aspect of the osteoma.
\n
\n
\n
3.2. Osteoid osteoma
\n
Osteoid osteoma is a benign bone-forming tumor characterized by small size, limited growth potential and disproportionate pain. Osteoid osteoma usually affects children and adolescents, although it is occasionally seen in older individuals. It is more common in males [2]. Osteoid osteoma is rarely described in TMJ [49].
\n
The trio of complaints for osteoid osteoma of the jaw is pain, swelling and tenderness [50].
\n
The most typical symptom of osteoid osteoma is spontaneous pain, usually responsive to non-steroidal anti-inflammatory drugs (NSAIDs). At first, the pain is light and discontinuous, but later becomes severe and constant [51].
\n
A characteristic radiographic finding is ‘nidus’, which represents a small, round, clear, non-calcified, well-demarcated radiolucency in the subjacent cortex surrounded by sclerotic bone, not larger than 2 cm [3]. CT and cone beam computed tomography (CBCT) are superior to MRI in diagnosing and precisely localizing these bone tumors in TMJ [46, 50].
\n
The differential diagnosis of osteoid osteoma is established which includes bone island/solitary enostosis, intracortical bone abscess (Brodie abscess), sclerosing forms of osteomyelitis and early diagnosis of osteosarcoma or osteoblastoma, fibroma or fibrous dysplasia [14, 51].
\n
However, the sequestrum of osteomyelitis is irregular rather than a well-demarcated round lesion and is usually located in the bone marrow, not in the cortical plate [50].
\n
The most important criterion to distinguish osteoid osteoma from osteoblastoma: osteoid osteomas are typically <1 cm in size, whereas osteoblast [52] stomas are generally >2 cm. An osteoid osteoma usually contains only a single calcification, whereas an osteoblastoma contains multiple calcifications. However, the osteoblastoma differs from the osteoid osteoma in that it has a greater growth potential, is frequently painless, and becomes heavily calcified when subjected to radiological examination [51].
\n
Surgical removal of the osteoid osteoma is the most advised treatment option if the pain is not relieved by NSAIDs. En bloc excision or cortical shaving and curettage of the nidus are sufficient and can provide immediate relief of symptoms. After the nidus is removed, all symptoms eventually disappear [46, 50, 53].
\n
\n
\n
3.3. Osteoblastoma
\n
Osteoblastoma is a rare benign bone-forming neoplasm which produces woven bone spicules, which are bordered by prominent osteoblasts. Osteoblastoma is uncommon, accounting for about 1% of all bone tumors and is more common in women and affects patients in the age range of 10–30 years [2]. The tumor normally involves the long bones, spine and sacrum. Less than 10% of osteoblastomas are located in the maxillofacial region [54, 55]. Osteoblastoma involving the TMJ is very rare [56].
\n
Complaints for osteoblastoma are dull persistent pain and swelling [57]. Even if NSAIDs is used, the pain will not decrease in contrast to osteoid osteoma [56].
\n
Osteoblastoma has identical histological features to osteoid osteoma [2]. Osteoblastomas are characterized by numerous plump osteoblastic cells producing and lining the haphazardly arranged lesional trabeculae of osteoid and woven bone. Numerous blood vessels are often seen in the osteoblastic and fibrous stroma filling the lesional inter-trabecular areas. Five scattered multinucleated giant cells resembling osteoclasts are also generally seen. Mitotic figures may be seen, but these are usually sparse and have a normal configuration [58]. Osteoblastoma and osteoid osteoma are histopathologically very similar, and diagnosis is often based on the size of the lesion, with an osteoid osteoma being less than 1 cm in diameter and an osteoblastoma being larger than 2 cm [59].
\n
The radiographic features are well-defined expansile lesions contain small scattered calcifications [59]. Radiographic differential diagnosis of osteoblastoma should include osteogenic sarcoma, chondrosarcoma, osteoid osteoma and aneurysmal bone cyst [3].
\n
The treatment choice of osteoblastoma for TMJ is conservative surgery. Recurrences after complete excision are uncommon [55].
\n
\n
\n
\n
4. Giant cell tumors
\n
Almost every lesion in the bone can contain giant cells, sometimes a large number. To be characterized as a giant cell tumor (GCT), the neoplasm must have oval mononuclear cells and more or less evenly distributed giant cells.
\n
\n
4.1. Giant cell tumor
\n
Giant cell tumors (GCTs) are a benign, locally aggressive neoplasm which is composed of sheets of neoplastic ovoid mononuclear cells interspersed with uniformly distributed large, osteoclast-like giant cells. GCT is classified as an “intermediate locally aggressive, rarely metastasizing” bone tumor by World Health Organization (WHO) [2]. The prevalence of GCTs peaks in adults in their 30s or 40s [60, 61]. GCTs are frequently identified at the epiphyses of long bones, particularly in the proximal tibia, distal femur and distal radius [62]. Craniofacial bone involvement is rare but has been reported to occur in the mandible, temporal bone, maxilla, occipital and sphenoid [63]. Less than 30 cases of GCT in the TMJ have been reported. Patients with GCTs at TMJ are presented with progressive pain and swelling. Due to compression or local invasion, hearing impairment, facial nerve paralysis, headache, visual area defects, double vision, visual loss, tinnitus, otalgia, vertigo and trismus can occur [64]. Discomforts as jaw locking, mandibular deviation and clicking can also be seen. These three symptoms and signs are also common with temporomandibular disorders [65].
\n
Recent experiments have characterized GCTs as consisting of three cell types: (1) osteoclast-like, multinucleated giant cells; (2) round mononuclear cells resembling monocytes and (3) spindle-shaped, fibroblast-like stromal cells [66].
\n
GCTs appear lytic, subarticular, eccentrically located and usually lack a sclerotic rim on radiographs. Local bony destruction, cortical breakthrough and soft tissue expansion may also be seen [67]. MRI is the preferred imaging modality for GCTs, as the diagnostic accuracy of MRI is high and it can detect soft tissue and intra-articular extension [68].
\n
Important differential diagnoses of GCTs are giant cell reparative granuloma, hyperparathyroidism, non-ossifying fibroma, chondroblastoma, solid areas of aneurysmal bone cyst, malignant fibrous histiocytoma and osteogenic sarcoma [69].
\n
Various modalities have been used in the treatment of GCTs including surgery, cryotherapy, radiotherapy, calcitonin, corticosteroids, a interferon and recently, the monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) denosumab [70, 71]. Intralesional curettage is not recommended for GCTs in the skull base because recurrence in this location would complicate further treatment and make it unresectable for reoperation [72]. However, because of the complexity of the craniofacial anatomy, wide excisions or en bloc resections for head and neck GCTs should be attempted. Radiotherapy can be applied for cases where wide excision cannot be achieved or for patients who are not fit for surgery [73]. But radiotherapy as a sole treatment modality is not recommended due to high (60–70%) recurrence rates [74]. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor can be used in recurrent and unresectable GCTs [75]. Denosumab specifically inhibits osteoclast-mediated bone destruction by GCTs [76]. Denosumab can be used to reduce the tumor size preoperatively [74].
\n
\n
\n
\n
5. Vascular tumors
\n
Primary vascular tumors are rare in bone. Hemangiomas occur as coincidental findings in the skull or spine. X-ray features are almost always diagnostic. They rarely cause clinical symptoms.
\n
\n
5.1. Hemangioma
\n
lntraosseous hemangiomas are benign vasoformative neoplasm or developmental condition of endothelial origin tumors occurring most often in the maxilla and mandible after the skull and vertebrae [2]. Clinically, hemangiomas of the mandible are often presented as slow-growing expansile lesions. They occur twice as often in women. Hemangiomas present as radiolucent lesions, which may have a unicystic- or multicystic-like “soap bubbly,” “honeycomb” or “trabeculated” appearance [77]. The differential diagnosis for this radiographic appearance must also include: ameloblastoma, odontogenic keratocyst, central giant cell granulomata, giant cell tumor of hyperparathyroidism, aneurysmal bone cyst and metastatic lesions [78]. Treatment may include embolization, sclerosing agents and surgery [79].
\n
\n
\n
\n
6. Lipogenic tumors
\n
Lipomas are rare in the bones and are found incidentally in the X-rays and contain calcaneus. Radiography shows a well-defined area of lucency with a central calcification area.
\n
\n
6.1. Intraosseous lipoma
\n
Lipoma of bone is a benign neoplasm of adipocytes that arises within the medullary cavity, cortex or on the surface of bone. Lipoma of bone is rare and accounts for less than 0.1% of primary bone tumors [2]. The jaw is its most uncommon bone location.
\n
Etiology of lipoma is not clear but possible etiological factors may be dental trauma, disruption of the post-extraction healing process, retention of radicular remains, medullary bone infarction (common in elderly) or osteoporotic bones [80, 81, 82]. They are generally asymptomatic, being diagnosed by chance during a radiographic examination. Symptoms depend on its size, location, time of evolution and growth rate. Pain, swelling and numbness may occur [83, 84]. Radiological appearance of intraosseous lipoma is well-circumscribed radiolucent unilocular or multilocular lesion. Treatment involves curettage of the lesion, with or without grafting the cavity [85].
\n
\n
\n
\n
7. Bone-related odontogenic tumors
\n
Odontogenic tumors are rare, some of them very rare, but they can be an important diagnostic and therapeutic problem.
\n
\n
7.1. Ossifying fibroma
\n
Ossifying fibroma (OF) is a well-demarcated lesion composed of fibrocellular tissue and mineralized material of varying appearances [86]. The mandible (especially the molar region) is affected more often than the maxilla [87]. Ossifying fibroma is mainly diagnosed between the second and fourth decades of life, with women being affected more frequently than men [88, 89]. Ossifying fibroma of craniofacial bones is composed of two components: fibrous stroma and bone elements that show various degrees of maturation [90]. The treatment of choice is surgical excision. Enucleation and curettage could be suitable for small and well-defined lesions; however, larger masses require radical surgery [91]. Condylectomy may be performed with an immediate TMJ reconstruction [92].
\n
\n
\n
\n
8. Fibrohistiocytic tumors
\n
Diffuse and localized forms of the giant cell tumor of the tendon sheath are more common with the descriptive category of fibrohistiocytic lesions.
\n
\n
8.1. Pigmented villonodular synovitis
\n
Pigmented villonodular synovitis (PVNS) is a rare, benign tumor but is a locally aggressive tumor of the synovial membrane with an annual incidence [93]. Lesions originate from the joint capsule, tendon sheath or bursae and occur most commonly in the knee, hip and ankle [94]. The etiology of PVNS is not clear and may result from chronic inflammation, trauma or represent a distinct neoplastic process [95, 96, 97]. It is considered as fibrohistiocytic tumor by the World Health Organization classification of bone and soft tissue tumors. Tenosynovial giant cell tumor, diffuse-type giant cell tumor, villonodular synovitis, giant cell tumor of the tendon sheath and nodular tenosynovitis are the synonyms of that tumor [2]. PVNS of the temporomandibular joint (TMJ) is a rare variant with less than 80 cases reported in the literature [98]. This slow-growing tumor may be seen in all age groups. The peak age of occurrence is between 30 and 50 ages [99]. PVNS has been shown to have a synovial cell origin immunophenotypically and is reported to involve myofibroblastic differentiation [100, 101]. The tumor is composed of monocyte, multinucleated giant cells and foam cells distributing in a fibrous stroma, presenting hemosiderin deposition [102]. It has a higher gender predilection in females [103].
\n
PVNS can enlarge into the middle cranial fossa, displacing the temporal lobe and invading the dura mater. Patients are generally present with an enlarging pre-auricular mass, pain, trismus or hearing loss [104]. The radiological appearance of PVNS on CT is a contrast-enhancing intra-articular lesion originating in the glenoid fossa, with focal areas of hyperdensity or cysts. It produces variable bony remodeling or erosion of the adjacent bone [105]. On MRI, the most characteristic finding is a mass with low signal intensity on T1 and GRE-T2 weighted sequences, reflecting the deposition of blood degradation products. Occasionally, hyperintense areas on T1 or GRE-T2 sequences may appear due to the presence of lipids or cysts, respectively [106].
\n
The differential diagnosis is established with osteoarthritic change, chondroblastoma, chondrosarcoma, aneurysmal bone cyst, rhabdomyosarcoma, plasmacytoma, cholesteatoma, intraosseous meningioma, reparative granuloma, tumoral calcium pyrophosphate dihydrate crystal deposition disease, chondroma of the tendon sheath, synovial chondromatosis, tendon sheath fibroma, synovial hemangioma, synovial sarcoma, embryonal rhabdomyosarcoma, giant cell granuloma, brown tumor and malignant fibrous histiocytoma [107, 108].
\n
Therapy for PVNS of the TMJ and temporal bone remains surgical. PVNS of the temporal bone most commonly acquires the diffuse form of disease involving the contiguous synovial space with extension into adjacent structures. Accordingly, limited resection or curettage carries a high rate of recurrence, whereas wide local resection, when feasible, is usually curative [104, 109]. The surgical approach must be carefully planned to allow for a complete removal of the tumor while minimizing surgical trauma [110].
\n
\n
\n
\n
9. Tumors of uncertain differentiation
\n
For tumors in this category, in most cases, there is no clear idea on the differentiation line (or normal cellular counterpart) that these lesions repeat.
\n
\n
9.1. Juxta-articular myxoma
\n
Juxta-articular myxoma is a rare, benign soft tissue tumor that usually arises in the vicinity of a large joint, has histological features resembling a cellular myxoma [2]. There are reported cases involving myxomas of the knee, shoulder, elbow, wrist and hip. To our knowledge, however, there is just one reported cases of juxta-articular myxomas of the temporomandibular joint (TMJ) [111]. The juxta-articular myxoma resembles the common myxoma, however, it is distinguished by its association with the underlying connective tissue components of the joint. These include the associated tendons, joint capsule, meniscus and synovium [112]. Palpable swelling is occasionally associated with pain, tenderness or a functional limitation may occur [113, 114]. Like the common myxoma, the treatment of choice for the juxta-articular myxomas is complete local excision [115]. Tumors extending into the infratemporal fossa are notoriously difficult to resect [116].
\n
\n
\n\n',keywords:"cartilage tumors, temporomandibular joint tumors, cartilage tumors, osteogenic tumors, osteochondroma, chondroma, chondroblastoma, pigmented villonodular synovitis, synovial chondromatosis, osteoma, juxta-articular myxoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/58184.pdf",chapterXML:"https://mts.intechopen.com/source/xml/58184.xml",downloadPdfUrl:"/chapter/pdf-download/58184",previewPdfUrl:"/chapter/pdf-preview/58184",totalDownloads:1313,totalViews:1581,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"June 7th 2017",dateReviewed:"November 8th 2017",datePrePublished:"December 20th 2017",datePublished:"February 28th 2018",dateFinished:null,readingETA:"0",abstract:"The temporomandibular joint (TMJ) forms a complex functional system with teeth, bones, connected muscles and ligaments. Any discomfort in any of these structures directly affects the joint. The complaints are mostly pain, malocclusion and swelling. Temporomandibular joint tumors are very uncommon but show symptoms similar to intra-articular disorders that make up most of these disorders. The most common TMJ-specific benign tumors are classified after a brief literature review. Our classification also includes the osteoma of the TMJ, other than World Health Organization’s (WHO) classification of soft tissue and bone tumors. This benign tumor was also included in the classification because of its higher frequency in the literature. The treatment of these neoplasms may be conservative or radical surgery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/58184",risUrl:"/chapter/ris/58184",book:{slug:"temporomandibular-joint-pathology-current-approaches-and-understanding"},signatures:"Mehmet Emre Yurttutan, Ayşegül Tüzüner Öncül and Hakan Alpay\nKarasu",authors:[{id:"178706",title:"Dr.",name:"Aysegul",middleName:null,surname:"Tuzuner Oncul",fullName:"Aysegul Tuzuner Oncul",slug:"aysegul-tuzuner-oncul",email:"ayltuzuner@yahoo.com",position:null,institution:{name:"Ankara University",institutionURL:null,country:{name:"Turkey"}}},{id:"213436",title:"Dr.",name:"Mehmet Emre",middleName:null,surname:"Yurttutan",fullName:"Mehmet Emre Yurttutan",slug:"mehmet-emre-yurttutan",email:"yurttutan@ankara.edu.tr",position:null,institution:{name:"Ankara University",institutionURL:null,country:{name:"Turkey"}}},{id:"213439",title:"Prof.",name:"Hakan Alpay",middleName:null,surname:"Karasu",fullName:"Hakan Alpay Karasu",slug:"hakan-alpay-karasu",email:"karasuhakan@hotmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cartilage tumors",level:"1"},{id:"sec_2_2",title:"2.1. Osteochondroma",level:"2"},{id:"sec_3_2",title:"2.2. Chondroma",level:"2"},{id:"sec_4_2",title:"2.3. Chondroblastoma",level:"2"},{id:"sec_5_2",title:"2.4. Synovial chondromatosis",level:"2"},{id:"sec_7",title:"3. Osteogenic tumors",level:"1"},{id:"sec_7_2",title:"3.1. Osteoma",level:"2"},{id:"sec_8_2",title:"3.2. Osteoid osteoma",level:"2"},{id:"sec_9_2",title:"3.3. Osteoblastoma",level:"2"},{id:"sec_11",title:"4. Giant cell tumors",level:"1"},{id:"sec_11_2",title:"4.1. Giant cell tumor",level:"2"},{id:"sec_13",title:"5. Vascular tumors",level:"1"},{id:"sec_13_2",title:"5.1. Hemangioma",level:"2"},{id:"sec_15",title:"6. Lipogenic tumors",level:"1"},{id:"sec_15_2",title:"6.1. Intraosseous lipoma",level:"2"},{id:"sec_17",title:"7. Bone-related odontogenic tumors",level:"1"},{id:"sec_17_2",title:"7.1. Ossifying fibroma",level:"2"},{id:"sec_19",title:"8. Fibrohistiocytic tumors",level:"1"},{id:"sec_19_2",title:"8.1. Pigmented villonodular synovitis",level:"2"},{id:"sec_21",title:"9. Tumors of uncertain differentiation",level:"1"},{id:"sec_21_2",title:"9.1. Juxta-articular myxoma",level:"2"}],chapterReferences:[{id:"B1",body:'\nFonseca RJ. Oral and Maxillofacial Surgery: Temporomandibular Disorders. USA: Saunders; 2000\n'},{id:"B2",body:'\nFlecther CDM, Unni KK, Mertens F. World Health Organization Classification of Tumours of Soft Tissue and Bone. IARC: Lyon; 2002\n'},{id:"B3",body:'\nRobert EM, Stern D. Oral and Maxillofacial Pathology, A Rationale for Diagnosis and Treatment. India: Quintessence; 2003\n'},{id:"B4",body:'\nAndrade NN, Gandhewar TM, Kapoor P, Thomas R. Osteochondroma of the mandibular condyle – Report of an atypical case and the importance of computed tomography. Journal of oral Biology and Craniofacial Research. 2014;4(3):208-213\n'},{id:"B5",body:'\nKurita K, Ogi N, Echiverre NV, Yoshida K. Osteochondroma of the mandibular condyle. A case report. International Journal of Oral and Maxillofacial Surgery. 1999;28(5):380-382\n'},{id:"B6",body:'\nMurphey MD, Choi JJ, Kransdorf MJ, Flemming DJ, Gannon FH. Imaging of osteochondroma: Variants and complications with radiologic-pathologic correlation. Radiographics: A Review Publication of the Radiological Society of North America, Inc. 2000;20(5):1407-1434\n'},{id:"B7",body:'\nGaines RE Jr, Lee MB, Crocker DJ. Osteochondroma of the mandibular condyle: Case report and review of the literature. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 1992;50(8):899-903\n'},{id:"B8",body:'\nKoole R, Steenks MH, Witkamp TD, Slootweg PJ, Shaefer J. Osteochondroma of the mandibular condyle. A case report. International Journal of Oral and Maxillofacial Surgery. 1996;25(3):203-205\n'},{id:"B9",body:'\nHenry CH, Granite EL, Rafetto LK. Osteochondroma of the mandibular condyle: Report of a case and review of the literature. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 1992;50(10):1102-1108\n'},{id:"B10",body:'\nSpahr J, Elzay RP, Kay S, Frable WJ. Chondroblastoma of the temporomandibular joint arising from articular cartilage: A previously unreported presentation of an uncommon neoplasm. Oral Surgery, Oral Medicine, and Oral Pathology. 1982;54(4):430-435\n'},{id:"B11",body:'\nKarasu HA, Ortakoglu K, Okcu KM, Gunhan O. Osteochondroma of the mandibular condyle: Report of a case and review of the literature. Military Medicine. 2005;170(9):797-801\n'},{id:"B12",body:'\nUtumi ER, Pedron IG, Perrella A, Zambon CE, Ceccheti MM, Cavalcanti MG. Osteochondroma of the temporomandibular joint: A case report. Brazilian Dental Journal. 2010;21(3):253-258\n'},{id:"B13",body:'\nMarchetti C, Mazzoni S, Bertoni F. Chondroma of the mandibular condyle-relapse of a rare benign chondroid tumour after 5 years’ follow-up: Case report. The British Journal of Oral & Maxillofacial Surgery. 2012;50(5):e69-e71\n'},{id:"B14",body:'\ndo Egito Vasconcelos BC, Porto GG, Bessa-Nogueira RV. Rare benign tumors of the mandibular condyle: Report of 2 cases and literature review. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2007;65(9):1830-1835\n'},{id:"B15",body:'\nHeitz C, Vogt BF, Bergoli RD, Hirsch WD, de Souza CE, Silva DN. Chondroma in temporomandibular region – Case report and therapeutic considerations. Oral and Maxillofacial Surgery. 2012;16(1):75-78\n'},{id:"B16",body:'\nChandu A, Spencer JA, Dyson DP. Chondroma of the mandibular condyle: An example of a rare tumour. Dento Maxillo Facial Radiology. 1997;26(4):242-245\n'},{id:"B17",body:'\nChang SE, Lee MW, Choi JH, Sung KJ, Moon KC, Koh JKA. Case of lingual chondroma. The British Journal of Dermatology. 1999;141(4):773-774\n'},{id:"B18",body:'\nDhirawani RB, Anand K, Lalwani G, Pathak S, Thakkar B. True chondroma of the mandibular condyle: A rare case. Annals of Maxillofacial Surgery. 2014;4(2):220-223\n'},{id:"B19",body:'\nFechner RE, Mills SE. Atlas of Tumor Pathology – Tumors of the Bones and Joints. Armed Forces Institute of Pathology: Washington, DC; 1993\n'},{id:"B20",body:'\nShintaku WH, Venturin JS, Langlais RP, Clark GT. Imaging modalities to access bony tumors and hyperplasic reactions of the temporomandibular joint. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2010;68(8):1911-1921\n'},{id:"B21",body:'\nLazow SK, Pihlstrom RT, Solomon MP, Berger JR. Condylar chondroma: Report of a case. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 1998;56(3):373-378\n'},{id:"B22",body:'\nPayne M, Yusuf H. Benign chondroblastoma involving the mandibular condyle. The British Journal of Oral & Maxillofacial Surgery. 1987;25(3):250-255\n'},{id:"B23",body:'\nJaffe HL, Lichtenstein L. Benign chondroblastoma of bone: A reinterpretation of the so-called calcifying or chondromatous giant cell tumor. The American Journal of Pathology. 1942;18(6):969-991\n'},{id:"B24",body:'\nVarvares MA, Cheney ML, Goodman ML, Ceisler E, Montgomery WW. Chondroblastoma of the temporal bone. Case report and literature review. The Annals of Otology, Rhinology, and Laryngology. 1992;101(9):763-769\n'},{id:"B25",body:'\nBui P, Ivan D, Oliver D, Busaidy KF, Wilson J. Chondroblastoma of the temporomandibular joint: Report of a case and literature review. 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Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2002;60(2):198-203\n'},{id:"B30",body:'\nKim SM, Hong SW, Ryu DJ, Huh JK. Chondroblastoma of the temporomandibular joint lateral capsule: A case report. Cranio: The Journal of Craniomandibular Practice. 2015;33(4):306-311\n'},{id:"B31",body:'\nMilgram JW. The classification of loose bodies in human joints. Clinical Orthopaedics and Related Research. 1977;124:282-291\n'},{id:"B32",body:'\nYokota N, Inenaga C, Tokuyama T, Nishizawa S, Miura K, Namba H. Synovial chondromatosis of the temporomandibular joint with intracranial extension. Neurologia Medico-Chirurgica. 2008;48(6):266-270\n'},{id:"B33",body:'\nHolmlund AB, Eriksson L, Reinholt FP. Synovial chondromatosis of the temporomandibular joint: Clinical, surgical and histological aspects. International Journal of Oral and Maxillofacial Surgery. 2003;32(2):143-147\n'},{id:"B34",body:'\nMankin HJ, editor. Synovial Chondromatosis in Pathophysiology of Orthopaedic Diseases. Rosemont, IL: American Academy Orthopaedic Surgeons; 2006\n'},{id:"B35",body:'\nPetito AR, Bennett J, Assael LA, Carlotti AE Jr. Synovial chondromatosis of the temporomandibular joint: Varying presentation in 4 cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2000;90(6):758-764\n'},{id:"B36",body:'\nGuarda-Nardini L, Piccotti F, Ferronato G, Manfredini D. Synovial chondromatosis of the temporomandibular joint: A case description with systematic literature review. International Journal of Oral and Maxillofacial Surgery. 2010;39(8):745-755\n'},{id:"B37",body:'\nPinto AA, Jr, Ferreira e Costa R, de Sousa SF, Chagas MR, do Carmo MA, de Lacerda JC. Synovial chondromatosis of the temporomandibular joint successfully treated by surgery. Head and Neck Pathology. 2015;9(4):525-529\n'},{id:"B38",body:'\nIonna F, Amantea M, Mastrangelo F, Ballini A, Maglione MG, Aversa C, et al. 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European Archives of Oto-Rhino-Laryngology: Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): Affiliated with the German Society for Oto-Rhino-Laryngology – Head and Neck Surgery. 2010;267(6):845-849\n'},{id:"B56",body:'\nJones AC, Prihoda TJ, Kacher JE, Odingo NA, Freedman PD. Osteoblastoma of the maxilla and mandible: A report of 24 cases, review of the literature, and discussion of its relationship to osteoid osteoma of the jaws. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2006;102(5):639-650\n'},{id:"B57",body:'\nRawal YB, Angiero F, Allen CM, Kalmar JR, Sedghizadeh PP, Steinhilber AM. Gnathic osteoblastoma: Clinicopathologic review of seven cases with long-term follow-up. Oral Oncology. 2006;42(2):123-130\n'},{id:"B58",body:'\nNeville B, Damm DD, Allen C, Chi A. Oral and Maxillofacial Pathology. 4 ed. Missouri: Elsevier; 2016\n'},{id:"B59",body:'\nEmanuelsson J, Allen CM, Rydin K, Sjostrom M. Osteoblastoma of the temporal articular tubercle misdiagnosed as a temporomandibular joint disorder. International Journal of Oral and Maxillofacial Surgery. 2017;46(5):610-613\n'},{id:"B60",body:'\nNishimura K, Satoh T, Maesawa C, Ishijima K, Sato H. Giant cell tumor of the larynx: A case report and review of the literature. American Journal of Otolaryngology. 2007;28(6):436-440\n'},{id:"B61",body:'\nvan der Heijden L, Dijkstra PD, van de Sande MA, Kroep JR, Nout RA, van Rijswijk CS, et al. The clinical approach toward giant cell tumor of bone. The Oncologist. 2014;19(5):550-561\n'},{id:"B62",body:'\nBibas-Bonet H, Fauze RA, Lavado MG, Paez RO, Nieman J. Garcin syndrome resulting from a giant cell tumor of the skull base in a child. Pediatric Neurology. 2003;28(5):392-395\n'},{id:"B63",body:'\nBertoni F, Unni KK, Beabout JW, Ebersold MJ. Giant cell tumor of the skull. Cancer. 1992;70(5):1124-1132\n'},{id:"B64",body:'\nFindlay JM, Chiasson D, Hudson AR, Chui M. Giant-cell tumor of the middle cranial fossa. Case report. Journal of Neurosurgery. 1987;66(6):924-928\n'},{id:"B65",body:'\nManfredini D, Guarda-Nardini L, Winocur E, Piccotti F, Ahlberg J, Lobbezoo F. Research diagnostic criteria for temporomandibular disorders: A systematic review of axis I epidemiologic findings. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2011;112(4):453-462\n'},{id:"B66",body:'\nWulling M, Engels C, Jesse N, Werner M, Delling G, Kaiser E. The nature of giant cell tumor of bone. Journal of Cancer Research and Clinical Oncology. 2001;127(8):467-474\n'},{id:"B67",body:'\nWang CS, Lou JH, Liao JS, Ding XY, LJ D, Lu Y, et al. Recurrence in giant cell tumour of bone: Imaging features and risk factors. La Radiologia Medica. 2013;118(3):456-464\n'},{id:"B68",body:'\nPurohit S, Pardiwala DN. Imaging of giant cell tumor of bone. Indian Journal of Orthopaedics. 2007;41(2):91-96\n'},{id:"B69",body:'\nZheng MH, Robbins P, Xu J, Huang L, Wood DJ, Papadimitriou JM. The histogenesis of giant cell tumour of bone: A model of interaction between neoplastic cells and osteoclasts. Histology and Histopathology. 2001;16(1):297-307\n'},{id:"B70",body:'\nLopez-Pousa A, Martin Broto J, Garrido T, Vazquez J. Giant cell tumour of bone: New treatments in development. Clinical & Translational Oncology: Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2015;17(6):419-430\n'},{id:"B71",body:'\nXu SF, Adams B, Yu XC, Xu M. Denosumab and giant cell tumour of bone-a review and future management considerations. Current Oncology (Toronto, Ont). 2013;20(5):e442-e447\n'},{id:"B72",body:'\nPrasad SC, Piccirillo E, Nuseir A, Sequino G, De Donato G, Paties CT, et al. Giant cell tumors of the skull base: Case series and current concepts. Audiology & Neuro-Otology. 2014;19(1):12-21\n'},{id:"B73",body:'\nChen ZX, DZ G, ZH Y, Qian TN, Huang YR, YH H, et al. Radiation therapy of giant cell tumor of bone: Analysis of 35 patients. International Journal of Radiation Oncology, Biology, Physics. 1986;12(3):329-334\n'},{id:"B74",body:'\nNicoli TK, Saat R, Kontio R, Piippo A, Tarkkanen M, Tarkkanen J, et al. Multidisciplinary approach to management of temporal bone giant cell tumor. Journal of Neurological Surgery Reports. 2016;77(3):e144-e149\n'},{id:"B75",body:'\nBranstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S, Thomas DM, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2012;18(16):4415-4424\n'},{id:"B76",body:'\nChawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: Interim analysis of an open-label, parallel-group, phase 2 study. The Lancet Oncology. 2013;14(9):901-908\n'},{id:"B77",body:'\nDelBalso AM, Banyas JB, Wild LM. Hemangioma of the mandibular condyle and ramus. AJNR – American Journal of Neuroradiology. 1994;15(9):1703-1705\n'},{id:"B78",body:'\nLund BA, Dahlin DC. Hemangiomas of the mandible and maxilla. Journal of Oral Surgery, Anesthesia, and Hospital Dental Service. 1964;22:234-242\n'},{id:"B79",body:'\nGuibert-Tranier F, Piton J, Riche MC, Merland JJ, Caille JM. Vascular malformations of the mandible (intraosseous haemangiomas). The importance of preoperative embolization. A study of 9 cases. European Journal of Radiology. 1982;2(4):257-272\n'},{id:"B80",body:'\nBarker GR, Sloan P. Intraosseous lipomas: Clinical features of a mandibular case with possible aetiology. The British Journal of Oral & Maxillofacial Surgery. 1986;24(6):459-463\n'},{id:"B81",body:'\nBasheer S, Abraham J, Shameena P, Balan A. Intraosseous lipoma of mandible presenting as a swelling. Journal of Oral and Maxillofacial Pathology: JOMFP. 2013;17(1):126-128\n'},{id:"B82",body:'\nHemavathy S, Roy S, Kiresur A. Intraosseous angiolipoma of the mandible. Journal of Oral and Maxillofacial Pathology: JOMFP. 2012;16(2):283-287\n'},{id:"B83",body:'\nBuric N, Krasic D, Visnjic M, Katic V. Intraosseous mandibular lipoma: A case report and review of the literature. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2001;59(11):1367-1371\n'},{id:"B84",body:'\nGonzalez-Perez LM, Perez-Ceballos JL, Carranza-Carranza A. Mandibular intraosseous lipoma: Clinical features of a condylar location. International Journal of Oral and Maxillofacial Surgery. 2010;39(6):617-620\n'},{id:"B85",body:'\nSanjuan A, Dean A, Garcia B, Alamillos F, Roldan E, Blanco A. Condylar intramedullary intraosseous lipoma: Contribution of a new case and review of the literature. Journal of Clinical and Experimental Dentistry. 2017;9(3):e498-e502\n'},{id:"B86",body:'\nBarnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC: Lyon; 2005\n'},{id:"B87",body:'\nVegas Bustamante E, Gargallo Albiol J, Berini Aytes L, Gay Escoda C. Benign fibro-osseous lesions of the maxillas: Analysis of 11 cases. Medicina oral, patologia oral y cirugia bucal. 2008;13(10):E653-E656\n'},{id:"B88",body:'\nSpeight PM, Carlos R. Maxillofacial fibro-osseous lesions. Current Diagnostic Pathology 2006;12:1-10\n'},{id:"B89",body:'\nEversole R, Su L, ElMofty S. Benign fibro-osseous lesions of the craniofacial complex. A review. Head and Neck Pathology. 2008;2(3):177-202\n'},{id:"B90",body:'\nYS F, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologic study. II. Osseous and fibro-osseous lesions, including osteoma, fibrous dysplasia, ossifying fibroma, osteoblastoma, giant cell tumor, and osteosarcoma. Cancer. 1974;33(5):1289-1305\n'},{id:"B91",body:'\nChang CC, Hung HY, Chang JY, CH Y, Wang YP, Liu BY, et al. Central ossifying fibroma: A clinicopathologic study of 28 cases. Journal of the Formosan Medical Association = Taiwan yi zhi. 2008;107(4):288-294\n'},{id:"B92",body:'\nZavattero E, Garzino-Demo P, Berrone S. Ossifying fibroma affecting the mandibular condyle: Report of an uncommon case. The Journal of Craniofacial Surgery. 2013;24(4):e351-e353\n'},{id:"B93",body:'\nMyers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: A clinical epidemiologic study of 166 cases and literature review. Medicine. 1980;59(3):223-238\n'},{id:"B94",body:'\nGranowitz SP, D’Antonio J, Mankin HL. The pathogenesis and long-term end results of pigmented villonodular synovitis. Clinical Orthopaedics and Related Research. 1976;114:335-351\n'},{id:"B95",body:'\nOehler S, Fassbender HG, Neureiter D, Meyer-Scholten C, Kirchner T, Aigner T. Cell populations involved in pigmented villonodular synovitis of the knee. The Journal of Rheumatology. 2000;27(2):463-470\n'},{id:"B96",body:'\nChoong PF, Willen H, Nilbert M, Mertens F, Mandahl N, Carlen B, et al. Pigmented villonodular synovitis. Monoclonality and metastasis – A case for neoplastic origin? Acta Orthopaedica Scandinavica. 1995;66(1):64-68\n'},{id:"B97",body:'\nVandeweyer E, Somerhausen ND, Andry G. Guess what! clinical course of the patient and histological findings. European Journal of Dermatology: EJD. 2000;10(8):639-640\n'},{id:"B98",body:'\nJoshi K, Huang B, Scanga L, Buchman C, Chera BS. Postoperative radiotherapy for diffuse pigmented villonodular synovitis of the temporomandibular joint. American Journal of Otolaryngology. 2015;36(1):106-113\n'},{id:"B99",body:'\nVogrincic GS, O’Connell JX, Gilks CB. Giant cell tumor of tendon sheath is a polyclonal cellular proliferation. Human Pathology. 1997;28(7):815-819\n'},{id:"B100",body:'\nCavaliere A, Sidoni A, Bucciarelli E. Giant cell tumor of tendon sheath: Immunohistochemical study of 20 cases. Tumori. 1997;83(5):841-846\n'},{id:"B101",body:'\nCarlson ML, Osetinsky LM, Alon EE, Inwards CY, Lane JI, Moore EJ. Tenosynovial giant cell tumors of the temporomandibular joint and lateral skull base: Review of 11 cases. The Laryngoscope. 2017;127(10):2340-2346\n'},{id:"B102",body:'\nSomerhausen NS, Fletcher CD. Diffuse-type giant cell tumor: Clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease. The American Journal of Surgical Pathology. 2000;24(4):479-492\n'},{id:"B103",body:'\nKisnisci RS, Tuz HH, Gunhan O, Onder E. Villonodular synovitis of the temporomandibular joint: Case report. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2001;59(12):1482-1484\n'},{id:"B104",body:'\nSafaee M, Oh T, Sun MZ, Parsa AT, McDermott MW, El-Sayed IH, et al. Pigmented villonodular synovitis of the temporomandibular joint with intracranial extension: A case series and systematic review. Head & Neck. 2015;37(8):1213-1224\n'},{id:"B105",body:'\nLe WJ, Li MH, Yu Q, Shi HM. Pigmented villonodular synovitis of the temporomandibular joint: CT imaging findings. Clinical Imaging. 2014;38(1):6-10\n'},{id:"B106",body:'\nKim KW, Han MH, Park SW, Kim SH, Lee HJ, Jae HJ, et al. Pigmented villonodular synovitis of the temporomandibular joint: MR findings in four cases. European Journal of Radiology. 2004;49(3):229-234\n'},{id:"B107",body:'\nStojadinovic S, Reinert S, Wildforster U, Jundt G. Destruction of the glenoid joint fossa by a tenosynovial giant-cell tumour of the skull base: A case report. International Journal of Oral and Maxillofacial Surgery. 1999;28(2):132-134\n'},{id:"B108",body:'\nRustin MH, Robinson TW. Giant-cell tumour of the tendon sheath – An uncommon tumour presenting to dermatologists. Clinical and Experimental Dermatology. 1989;14(6):466-468\n'},{id:"B109",body:'\nDamodar D, Chan N, Kokot N. Pigmented villonodular synovitis of the temporomandibular joint: Case report and review of the literature. Head & Neck. 2015;37(12):E194-E199\n'},{id:"B110",body:'\nCarlson ML, Osetinsky LM, Alon EE, Inwards CY, Lane JI, Moore EJ. Tenosynovial giant cell tumors of the temporomandibular joint and lateral skull base: Review of 11 cases. The Laryngoscope. 2016\n'},{id:"B111",body:'\nYe ZX, Yang C, Chen MJ, Wilson JJ. Juxta-articular Myxoma of the temporomandibular joint. The Journal of Craniofacial Surgery. 2015;26(8):e695-e696\n'},{id:"B112",body:'\nAllen PW. Myxoma is not a single entity: A review of the concept of myxoma. Annals of Diagnostic Pathology. 2000;4(2):99-123\n'},{id:"B113",body:'\nSomford MP, de Vries JS, Dingemans W, de Jonge M, Maas M, Schaap GR, et al. Juxta-articular myxoma of the knee. The Journal of Knee Surgery. 2011;24(4):299-301\n'},{id:"B114",body:'\nKorver RJ, Theunissen PH, van de Kreeke WT, van der Linde MJ, Heyligers IC. Juxta-articular myxoma of the knee in a 5-year-old boy: A case report and review of the literature (2009: 12b). European Radiology. 2010;20(3):764-768\n'},{id:"B115",body:'\nTse JJ, Vander S. The soft tissue myxoma of the head and neck region – Report of a case and literature review. Head & Neck Surgery. 1985;7(6):479-483\n'},{id:"B116",body:'\nMansour OI, Carrau RL, Snyderman CH, Kassam AB. Preauricular infratemporal fossa surgical approach: Modifications of the technique and surgical indications. Skull Base: Official Journal of North American Skull Base Society. 2004;14(3):143-151 discussion 51\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mehmet Emre Yurttutan",address:"yurttutan@ankara.edu.tr",affiliation:'
Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Ankara University, Ankara, Turkey
Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Ankara University, Ankara, Turkey
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1. Introduction
Glucagon is a 29-amino acid peptide hormone secreted by pancreatic α-cells and interacts with specific receptors located in various organs, where it activates the glycogenolysis and gluconeogenic pathways, resulting in raised blood glucose levels [1, 2, 3]. Glucagon tends to form gel-like fibrillar aggregates in acidic condition [4]. These aggregates are cytotoxic due to the activation of apoptotic signaling pathways [5]. These fibrils are similar to those of other therapeutic peptides and proteins such as human calcitonin (hCT) [6] and insulin [7] and pathologically related fibrils such as prion [8], amylin (type 2 diabetes) [9], β-amyloid (Alzheimer’s disease) [10], and polyglutamine [11].
Some non-fibrillar proteins and peptides have been observed by electron microscopy to form amyloid fibrils with similar morphologies [12]. Several characteristics of these fibrils are related to the misfolding of proteins, leading to severe conditions such as fibril deposits in the brains of Alzheimer’s disease patients [13] and in the pancreas of patients with type 2 diabetes [9].
Kinetic analyses of fibril formation by the therapeutic peptide human calcitonin indicate that hCT molecules associate to form fibril intermediates via a two-step autocatalytic reaction mechanism. The first step of kinetic reaction (rate constant, k1) is a homogeneous reaction from micelle-like oligomers to fibril intermediates. These intermediates react with monomeric molecules to elongate into longer fibrils via a heterogeneous fibril elongation process (rate constant, k2) [14, 15, 16, 17]. Elucidating the molecular structure of amyloid fibrils is important for understanding the mechanism of self-aggregation, but it is difficult to determine high-resolution molecular structures using typical spectroscopic methods because fibrils are heterogeneous solids. Solid-state NMR spectroscopy has demonstrated advantages for the conformational determination of Alzheimer’s amyloid β-peptides (Aβ), which mainly comprise 40 or 42 amino acid residues and are the main component of the amyloid plaques found in Alzheimer’s disease patients [12, 18]. Both the intra-chain conformation of the Aβ molecule in fibrils and their intermolecular alignment have been analyzed to explore the mechanism of molecular association underlying the formation of Aβ (1–40) [19, 20, 21] and the more toxic Aβ (1–42) [22, 23, 24] fibrils.
The primary structure of the glucagon peptide is His1-Ser-Gln-Gly-Thr5-Phe-Thr-Ser-Asp-Tyr10-Ser-Lys-Tyr-Leu-Asp15-Ser-Arg-Arg-Ala-Gln20-Asp-Phe-Val-Gln-Trp25-Leu-Met-Asn-Thr-OH.
An X-ray crystallographic study showed that glucagon adopts a trimeric α-helix structure stabilized by hydrophobic interactions between molecules related by threefold symmetry [25], whereas a solution NMR study showed that glucagon in dilute aqueous solution may not form a specific structure, with the exception of the 22–25 region [26]. The secondary structure of glucagon in the presence of dodecylphosphocholine micelles comprises three turns of an irregular α-helix formed by residues 17 to 29 near the C-terminus, a stretch of extended polypeptide chain from residues 14 to 17, an α-helix-like turn formed by residue 10 to 14, and another extended region from residue 5 to 10 [27].
Fibril formation by glucagon molecules was observed by Beaven et al. in undisturbed aqueous solution at pH 2 [4]. The viscosity initially increased and a birefringent gel is formed. With time, a precipitate appeared comprising long fibrils, as determined using electron microscopy. Infrared spectra of the gel, solid film, and precipitate showed that in all these states, glucagon is in the form of antiparallel β-sheet chains [5, 28]. Kinetic analysis of fibril formation by glucagon under acidic conditions demonstrated a complex fibrillation mechanism in which suitable changes in the fibrillation condition can alter the type of fibril formed or result in the formation of a mixture of several types of fibrils [29, 30]. Furthermore, the fibrils come in two forms: one composed entirely of glucagon monomers and the other entirely of glucagon trimers [31]. Studies of fibril formation typically use acidic pH solutions because of the low solubility of glucagon in neutral solution.
Understanding the cytotoxicity of amyloid-forming peptides requires investigating the interaction of these peptides with membranes because lipid bilayer components dramatically alter most aspects of amyloid aggregation [32, 33, 34, 35]. We previously reported glucagon fibrillation in the presence of dimyristoylphosphatidylcholine/1,2-dihexanoyl-sn-glycero-3-phophocholine (DMPC-DHPC) bicelles in acidic solution. The glucagon structure in the fibril in the presence of these bicelles is different from that in their absence [36]: the N- and C-termini both change from α-helix to β-sheet in acidic solution, while the N-terminus remains in an α-helical conformation, whereas the C-terminus changes from α-helix to β-sheet in the presence of bicelles. The nucleation rate is slower, and the fibril elongation rate is faster in acidic solution than in the presence of bicelles.
In neutral conditions, glucagon molecules are incorporated into lipid bilayers above the phase transition temperature, and the properties of the lipids appear to remain unperturbed. Below the phase transition temperature, glucagon forms discoidal particle with DMPC [37, 38] and induces closer packing of the phospholipid bilayers [39]. Similar peptide-lipid interaction to form discoidal particles below the phase transition temperature is seen in the melittin-DMPC bilayer system [40, 41].
The time course behavior of glucagon fibril formation inside a DMPC bilayer under neutral conditions, which approximates the physiological condition, and the kinetic behavior of glucagon under these conditions have been investigated to understand the fibrillation process under near-physiological conditions [42].
2. Fibril formation by glucagon in acidic solution
Gel formation by glucagon in the β-sheet conformation in acid solutions is a relatively slow process at room temperature [4] and can be followed by observing the change in viscosity as shown in Figure 1. The most marked feature of the change in viscosity in these time profiles is the presence of a substantial lag phase during which oligomeric nuclei are likely formed and function as initiation sites. These phenomena were confirmed by adding a small seed of preformed glucagon gel on the end of a wire into a viscometer containing a fresh acidic glucagon solution. The viscosity increased immediately with essentially no lag (Figure 1a). After a prolonged reaction time, the viscosity began to decrease and fibrils sometimes precipitated. These fibrils represent a variant of the β-structure of glucagon.
Figure 1.
Time course behavior of glucagon aggregation in 0.01 M hydrochloric acid at 26°C and a glucagon concentration of 2.5 mg/ml. (a) Time course of reduced viscosity (msp/c); glucagon with no addition (○); glucagon seeded with preformed gel (□); glucagon solution containing 5% by volume dioxin (●). (b) Effect of glucagon concentration at 4 mg/ml (□); 2.5 mg/ml (○); and 1 mg/ml (●). (c) Effect of temperature on the aggregation rate of glucagon at a glucagon concentration of 2.5 mg/ml at 26°C (○); 30°C (□); and 35°C (∇) (ref. [4]).
Fibril formation strongly depends on the peptide concentration, proceeding very slowly at less than about 1.5 mg/ml and occurring more readily at higher concentration (Figure 1b). Increasing the ionic strength of the solution results in both an increasing aggregation rate and more rapid production of fibrils. The change in viscosity with time in even 0.01 M sodium chloride occurs much more rapidly than in the absence of salt, and viscosity decreases quickly.
The effect of temperature on the polymerization rate is also very marked. Both the aggregation rate and the size of the aggregates as reflected in the maximal values of the reduced viscosity show a strong temperature maximum around 30°C (Figure 1c). An addition of 5% (v/v) of the nonaqueous solvent dioxin completely inhibits the aggregation (Figure 1a).
Transmission electron microscopy (TEM) time-elapsed pictures were obtained during fibril formation by glucagon dissolved in 0.015 M acetic acid solution (18 mg/ml) at pH 3.3 [36]. TEM pictures were measured approximately 2 hrs, then 1 week, and 6 months after the dissolution of glucagon (Figure 2). A small number of spherical-shaped fibril intermediates appeared after approximately 2 hrs, as shown in Figure 2a. After 1 week, the number of spherical fibril intermediates had increased, and elongated fibrils had appeared (Figure 2b). After 6 months, long mature fibrils about 10 nm in diameter were observed, and the spherical fibril intermediates had completely disappeared (Figure 2c).
Figure 2.
Transmission electron micrographs of glucagon (18 mg/ml) in 0.015 M acetic acid solution at pH 3.3. (a) Taken approximately 2 hrs after the dissolution of glucagon. The bar indicates 20 nm. (b) Taken 1 week after dissolution of glucagon. The bar indicates 50 nm. (c) Taken 6 months after dissolution of glucagon. The bar indicates 50 nm (ref. [36]).
The α-helical content of aged glucagon at 5.0 mg/ml decreased significantly to approximately 1%. The CD spectrum of a β-sheet structure typically shows an intense positive band at 198 nm and a negative band at 218 nm [5]. The CD spectral pattern of aged glucagon was that of a β-sheet structure, indicating a conformational transition from α-helical to β-sheet structure under these conditions.
The FTIR spectrum of glucagon immediately after dissolution showed a low-intensity β-sheet band at 1620–1630 cm−1, and aging resulted in progressively greater amounts of β-sheet [28]. Deconvolution and curve fitting of the amide I band showed that unaged glucagon contained 54% α-helix/random coil structure and 2% β-sheet structure, whereas aged glucagon comprised 22% α-helix/random coil structure and 49% β-sheet structure.
Detailed kinetic, spectroscopic, and morphological studies have revealed that glucagon can form several types of fibrils that differ at the level of molecular packing of the peptide [29, 30, 31, 43, 44, 45, 46]. Each type forms through distinct nucleation-dependent aggregation pathways influenced by the solution conditions and can be self-propagated by seeding. Type A fibrils that form at high glucagon concentration (>5 mg/ml, pH 2.5) represent the least stable fibril type with a low melting midpoint (Tmapp < 32°C) and single protofilament fibrils observable by TEM (Figure 3a). Type B (Bunagitated and Bagitated) fibrils form under low glucagon concentration (<0.5 mg/ml, pH 2.5). Type Bunagitated fibrils grow by branching in the absence of agitation and appear as branched twisted fibrils by TEM (Figure 3b). Type Bagitated glucagon fibrils form when the solution is agitated, suggesting that agitation breaks the fibril creating more free fibril ends that align as parallel pairs (Figure 3c). Type D fibrils grow under low glucagon concentration (<0.5 mg/ml, pH 2.5) in the presence of 150–250 mM Cl− and are twisted and tightly packed (Figure 3d). Type S fibrils grow under low glucagon concentration (<0.5 mg/ml, pH 2.5) in the presence of 1 mM Na2SO4 (7:1 ratio with glucagon) and appear as twisted mature fibrils by TEM (Figure 3e).
Figure 3.
Electron microscope image of morphology of different types of glucagon fibrils. The scale bar is 50 nm. (a) Type A: The glucagon concentration, >5 mg/ml, 50 mM glycine, pH 2.5, low agitation. (b) Type Bunagitated: Glucagon concentration, <0.5 mg/ml, 50 mM glycine, pH 2.5, low agitation. (c) Type Bagitated: Glucagon concentration, <0.5 mg/ml, 50 mM glycine, vigorous agitation. (d) Type D: Glucagon concentration, <0.5 mg/ml, 50 mM glycine, pH 2.5+, 150–250 mM Cl−. (e) Type S: Glucagon concentration, <0.5 mg/ml, 0.01 N HCl, 1 mM SO42− (ref. [30]).
Solid-state 13C NMR spectra were observed for 18 mg/ml [1-13C]Gly4 and [3-13C]Ala19-glucagon in 0.015 M acetic acid solution, pH 3.3 [36]. The 13C direct excitation with dipolar decoupling and magic angle spinning (DD-MAS) signal indicates monomeric glucagon, and the 13C cross polarization with magic angle spinning (CP-MAS) signal indicates fibril glucagon. The DD-MAS spectra (Figure 4A and C) of [1-13C]Gly4 and [3-13C]Ala19 exhibit signals at 171.7 and 16.4 ppm, respectively, consistent with the monomeric state and indicate that the region near the Gly4 and Ala19 residues forms α-helix structures, as shown by the conformationally dependent chemical shift values [47, 48, 49]. The experimentally determined chemical shift values and secondary structures are summarized in Table 1. The 13C CP-MAS spectra of [1-13C]Gly4 and [3-13C]Ala19 (Figure 4B and D) of glucagon in the fibril state exhibit signals at 167.2 and 21.0 ppm, respectively, and indicate that the vicinities of Gly4 and Ala19 form β-sheet structures.
Figure 4.
13C DD-MAS and CP-MAS NMR spectra of [1-13C]Gly4 (A and B) and [3-13C]Ala19 (C and D) of [1-13C]Gly4 and [3-13C]Ala19-glucagon in acetic acid solution at pH 3.3. Schematic structures of glucagon in the monomeric and fibril states (right panels) (ref. [36]).
Fibril formation condition
Fibril type
[1-13C]Gly4 (structure)
[3-13C]Ala19 (structure)
Ref.
Acidic solution (0.015 M acetic acid solution pH 3.3)
Structural transitions during glucagon fibrillation in various conditions as determined by conformation-dependent 13C chemical shifts (ppm)*.
The structure around each amino acid residues was determined by comparing the experimentally obtained 13C chemical shift values (δiso) with typical 13C chemical shift values (δiso) of α-helix and β-sheet, reported as 171.6 and 168.5 for [1-13C]Gly and 14.9 and 19.9 for [3-13C]Ala, respectively [47, 48, 49].
Conformationally dependent chemical shift values [47, 48, 49] clearly indicate that the N-terminus of monomeric glucagon forms an α-helix structure, the center portion forms a random coil, and the C-terminus forms an α-helix structure, as shown in Table 1 and Figure 4 (right panels) in acetic acid solution. When the glucagon monomer aggregates to form fibrils, the N-terminal and C-terminal regions change from an α-helix to a β-sheet as seen with other amyloid-forming peptides such as human calcitonin [14] in acetic acid solution.
3. Cytotoxicity of glucagon fibril
The cytotoxicity of the glucagon fibril was assessed by exposing PC12 and NIH-3 T3 cells to 0.1–100 μM peptide aggregate for 72 hrs followed by cell viability determination under the WST-8 assay and released lactate dehydrogenase (LDH) [5]. A significant decrease in cell viability was observed in cultures exposed to 10–100 μM aged glucagon (P < 0.01) but not in cultures treated with 100 μM nonaged glucagon. It was determined whether the loss of cell viability was due to cell death by measuring the release of LDH. Treatment with 10 μM aged glucagon induced a significant increase in LDH release compared to control, whereas no significant increase in LDH release was observed in cultures treated with 100 μM nonaged glucagon or 1 μM or lower aged glucagon. Thus, glucagon fibrils were found to be highly toxic to PC12 cells, similar to the case of aged prion protein fragment (PrP)106–126 [50] and β-amyloid (Aβ)1–42 [51] (>10 mM). Aged salmon calcitonin also displayed significant cytotoxicity in PC12 cells, whereas nonaged salmon calcitonin did not induce significant cell death [5].
Next, signaling pathways for the cytotoxicity of peptide fibrils were investigated [5]. Caspase-3 activation is required for the early stages of apoptosis that include DNA fragmentation and morphological changes. To determine whether aged glucagon induces caspase-3 activation in PC12 cells, cells were exposed to 50 μM aged glucagon, and the caspase-3-like activities of the cell lysates were measured by cleavage of the fluorometric caspase-3 substitute Z-DEVD-rhodamine 110. The activity increased prior to the loss of membrane integrity, and 24 hrs after incubation, maximum caspase-3 activity was detected (160% of the control level). In contrast, no significant elevation of casepase-3 activity was observed in cells treated with 50 μM nonaged glucagon. These results indicate that the exposure of PC12 cells to peptide fibrils induces a rapid (within 24 hrs) and significant elevation in casepase-3 activity prior to the loss of cell viability 72 hrs after exposure.
In summary, the misfolding of the therapeutic peptide glucagon generates amyloidogenic fibrils, leading to cytotoxicity mediated by the activation of the apoptotic enzyme caspase-3 in vitro.
4. Kinetic analysis of the glucagon fibrillation process
As shown in Figure 5, glucagon monomers (A) first aggregate to form weakly coupled oligomers (An) akin to the micelle state. Next, glucagon oligomers (An) form fibril intermediates (nuclei) (Bn) through a homogeneous nucleation process with a rate constant k1. Fibril intermediates (Bn) then react with monomer (A) to form elongated fibrils with a rate constant k2. This is called the inhomogeneous fibril elongation process. The B form plays a role in the catalysis of A to B, and therefore this is an autocatalytic reaction. Since the nucleation and elongation processes are rate-determining steps, fibril formation is a two-step autocatalytic reaction.
Figure 5.
Schematic of the glucagon fibril formation process in acidic solution. Several monomers (A) aggregate to form weakly coupled micelles (An). Micelles (An) form a fibril nucleus (Bn) through a homogeneous nucleation process with a rate constant k1. Fibril nuclei react with monomers (A) to form elongated fibrils (Bn + 1) with a rate constant k2. In this reaction, B acts as a catalyst to change the A form to the B form. Overall, this fibril formation reaction is a two-step autocatalytic reaction mechanism.
The rate constants of glucagon fibril formation were determined by observing the signal intensities of [1-13C]Gly4 in [1-13C]Gly4 and [3-13C]Ala19-glucagons by 13C CP-MAS NMR spectroscopy with time (Figure 6A and B). The signal intensities increased after a delay time. The increase in 13C CP-MAS signal intensities corresponds to the increase in fibril components, and thus we obtained the rate constants, k1 and k2, for the two-step autocatalytic reaction mechanism, in which k1 is the rate constant for the fibril nucleation process and k2 is the rate constant for the fibril elongation process [14].
Figure 6.
(A) Time course of changes in the 13C CP-MAS and DD-MAS signals of [1-13C]Gly-glucagon during the fibril formation processes [36]. (B) Plot of normalized CP-MAS signal intensity against elapsed time for glucagon fibril formation in acidic solution at pH 3.3 [36]. (C) Plot of normalized turbidity intensities against elapsed time for glucagon fibril formation in neutral solution (20% acetonitrile solution, pH 7.5) [42].
The first reaction step is homogeneous nuclear formation given by
Ano→k1Bno,E1
where Ano is the micelles formed by no number of A-form glucagon monomers and Bno is the fibrils formed by no number of B-form glucagon fibrils. The kinetic equation for Reaction (1) can be given by
df/dt1=k11−f,E2
where f is the fraction of B-glucagon fibrils in the system.
The second heterogeneous fibril elongation reaction can be given by k2
A+Bn→k2Bn+1,E3
where Bn and Bn + 1 are elongated fibrils with n and n + 1 number of B-form glucagons. The relevant kinetic equation is given by
df/dt2=k2af1−f,E4
where a is the initial concentration of glucagon. The overall kinetic equation can be given by
where f is the fraction of glucagon molecules in the fibril form at time t and ρ represents a dimensionless value describing the ratio of k1 (the rate constant for the first nucleation process) to k, namely, ρ = k1/k and k = ak2 (k2 is the rate constant for the second elongation process of the fibrils, and a is the initial peptide concentration) [14]. The best fits of Eq. (6) are shown in Figure 6B (solid lines), and the analyzed rate constants are summarized in Table 2. The k1 and k2 values were obtained experimentally from the intensity variation of the 13C CP-MAS NMR signals of [1-13C]Gly4 as shown in Figure 6B and Table 2 for glucagon in acidic solution. In comparison, rate constants of fibril formation were obtained for glucagon in neutral solution by plotting the turbidity of the solution against the elapsed time by using an established protocol [52] (Figure 6C).
Rate constants for glucagon fibril nucleation (k1) and fibril elongation (k2) for a two-step autocatalytic reaction mechanism under a variety of conditions.
The intensity of the 13C CP-MAS NMR signal of [1-13C]Gly4 was plotted against the elapsed time for glucagon in the presence of bicelles in acidic solution and for glucagon embedded inside lipid bilayers in neutral solution. The obtained rate constants are given in Table 2.
5. Fibril formation by glucagon in the presence of bicelles in acidic solution
In the presence of bicelles (DMPC-DHPC; 3:1), the N-terminus of glucagon forms an α-helix, the center portion forms a random coil, and the C-terminus forms an α-helix in the monomeric state (Table 1). In contrast to glucagon in acetic acid solution, the aggregation of monomers into the fibrils in the presence of bicelles results in the N-terminus maintaining an α-helix structure and the center portion remaining in a random coil structure, whereas the C-terminus changes from an α-helix to a β-sheet structure (Figure 7 and Table 1). There is therefore significant difference in the structural transition between monomer and fibril in the presence and absence of bicelles, since the N-terminus maintains an α-helix structure in the process of fibril formation in the presence of bicelles. This result suggests that the N-terminal portion of a glucagon fibril significantly interacts with the lipid bilayer surface.
Figure 7.
Schematic diagram of the fibrillation processes of glucagon in acetic acid solution (left) and acidic solution in the presence of bicelles (center). (A) Monomeric form. (B) Weakly coupled oligomer. (C) Fibril intermediate. (D) Elongated fibril. TEM pictures of glucagon fibril intermediates with ellipsoidal shapes and of disk-type bicelles are seen in the top right photo. An elongated fibril is seen attached by its end to a bicelle in the bottom right photo (ref. [36]).
The above findings provide insights into the mechanism of fibril formation in the presence and absence of lipid bilayers, as shown in Figure 7. In the absence of lipid bilayers, monomers may aggregate with each other to form oligomeric intermediates (similar to micelles) through a homogeneous reaction (Figure 7B; left), likely driven by the amphipathic natures of the N-terminal and C-terminal α-helices. These oligomeric intermediates then change into spherical fibril intermediates (Figure 7C; left) as observed by TEM (Figure 2a and b). Subsequently, these spherical fibril intermediates may form fibril nuclei and interact with monomeric glucagon to allow elongation of the fibril by changing from an α-helix to a β-sheet through a heterogeneous elongation process (Figure 7D; left).
In the presence of lipid bilayers, monomers form a structure similar to that in the absence of lipid bilayers. The monomers likely associate quickly with the lipid bilayer and subsequently associate with other monomers to form weakly coupled oligomeric intermediates (Figure 7B; right). These oligomeric intermediates may change their structure to form fibril intermediates on the surface of the lipid bilayer and are observed as ellipsoid-shaped fibril intermediates (Figure 7C; right and TEM picture) on the surface of the lipid bilayer. The elliptical shape is due to the N-terminal region retaining an α-helix structure even in the fibril intermediates. The fibril intermediates grow into longer fibrils on the surface of the lipid bilayer and protrude outside the lipid bilayers, as shown schematically in Figure 7D (right) and in the TEM picture (Figure 7D; right bottom).
The k1 rate constant for nuclear formation in the presence of lipid bilayers is faster than in the absence of lipid bilayers (Table 2) because glucagon monomers associate with the surface of the lipid bilayer, migrate laterally on the surface of the lipid bilayer to form oligomeric intermediates, and then subsequently change to fibril intermediate through a homogeneous nucleation reaction. This two-dimensional process may be faster than nuclear formation in the three-dimensional solution state.
The k2 rate constant for fibril elongation in the presence of lipid bilayers is slower than in the absence of lipid bilayers. As discussed previously, the N-terminal part of the glucagon molecule in a fibril in the presence of a lipid bilayer remains in an α-helix which may be stabilized when the helix interacts with the lipid bilayer. However, after the fibril grows and is released from the lipid bilayer, the N-terminal α-helix becomes more unstable than the N-terminal β-sheet formed in a fibril that protrudes from the lipid bilayer. This unstable fibril can grow to the outside of the lipid bilayer because it potentially acts as a template to form structures identical to the fibril nuclei formed on the surface of the lipid bilayer. The instability of the fibril state outside the lipid bilayer results in a decrease in the k2 value for fibril elongation as compared to the absence of a lipid bilayer.
These results show that glucagon molecules significantly interact with lipid bilayers during the fibril formation processes. To understand the fibril formation process under physiological condition, a variety of lipid bilayer systems including a lipid bilayer in neutral solution were investigated.
6. Fibrillation mechanism of glucagon inside the lipid bilayer in the neutral condition
Fibril formation processes were investigated for glucagon embedded inside a lipid bilayer in neutral solutions (i.e., essentially physiological conditions) [42]. Glucagon-induced morphological changes of lipid bilayers and fibril formation process in a glucagon containing lipid bilayer are shown in Figure 8. The monomers may aggregate with each other to form oligomers (Figure 8B) likely driven by the amphipathic nature of the N-terminal and C-terminal α-helices. These oligomers then change into ellipsoidal fibril intermediates (nuclei) (Figure 8C) through a homogeneous reaction, as observed by TEM (Figure 8C, bottom). At this stage, the glucagon intermediates strongly interact with the lipid bilayer to form discoidal lipid bilayer particles. Subsequently, this ellipsoidal fibril intermediate (nucleus) interacts with monomeric glucagon inside the lipid bilayer to allow elongation of the fibril by changing from an α-helix to a β-sheet through a heterogeneous elongation process (Figure 8D). After a long time standing, fibril networks are formed, and lipid molecules are compartmentalized (Figure 8E), resulting in increased lipid molecule mobility and the induction of a gel-like state throughout the sample, now in an amyloidogenic gel state [53, 54].
Figure 8.
Schematic diagrams of the morphological states of glucagon-DMPC bilayer systems (DMPC/glucagon; 50/1) at temperatures above and below the phase transition temperature (Tc = 23°C for DMPC). (A) Glucagon-DMPC bilayer state 1 day after sample preparation. (B) Glucagon-DMPC bilayer state 2 days after sample preparation. (C) Glucagon-DMPC bilayer state 4 days after sample preparation with the corresponding TEM picture shown below. (D) Glucagon-DMPC bilayer state 7 days after sample preparation with the corresponding TEM picture shown below. (E) Glucagon-DMPC bilayer system 10 days after sample preparation. The corresponding TEM picture is shown below (ref. [42]).
The kinetic of fibrillation was thus analyzed using a two-step autocatalytic mechanism as summarized in Table 2. The k1 rate constant for nuclear formation in neutral solution is much slower than that in a DMPC bilayer in neutral conditions (Table 2). In a DMPC/glucagon bilayer, glucagon molecules are condensed inside the DMPC bilayer, and thus the nucleation rate of glucagon in a DMPC/glucagon bilayer is much faster than that in neutral solution. The k1 rate constant for nuclear formation in a lipid bilayer in a neutral solution is slower than in a lipid bilayer in an acidic solution. In an acidic solution, glucagon locates on the surface of lipid bilayer and then migrates laterally on the surface of the lipid bilayer to form oligomers and subsequently changes to fibril nuclei through homogeneous nucleation reaction. In contrast, glucagon is deeply embedded inside a lipid bilayer in neutral solution and thus migrates more slowly inside the lipid bilayer, as reflected in the lower k1 value.
The k2 rate constant for the elongation of glucagon fibrils in a DMPC/glucagon bilayer is much slower than that in neutral solution. Glucagon molecules in a DMPC/glucagon bilayer interact strongly with the DMPC bilayer. It therefore takes a long time to disrupt the interaction with the lipid bilayer and form interaction with glucagon fibrils. The k2 rate constant for fibril elongation in the presence of lipid bilayers under neutral condition is significantly slower than that in lipid bilayers under acidic conditions. Under neutral conditions, glucagon is embedded deep inside the lipid bilayer, and hence it takes longer to release monomeric glucagon from the lipid bilayer. Therefore, the k2 values for fibril elongation decrease as compared to the case in a lipid bilayer in acidic conditions.
7. Conclusions
It is demonstrated that glucagon forms fibrils in acidic solution and in the presence of lipid bilayer (bicelle) in acidic solution. Glucagon aggregates to form fibril intermediates that glow into elongated fibrils. Glucagon intermediates are formed on the surface of the lipid bilayer in the presence of bicelle. These fibrils are cytotoxic through their activation of apoptotic processes, similar to β-amyloid and salmon calcitonin. Kinetic analyses of glucagon fibril formation are performed using a two-step autocatalytic reaction mechanism comprising fibril nucleation and elongation processes. It is revealed that glucagon forms fibril intermediates and grows into elongated fibrils inside the lipid bilayer under neutral conditions. These properties of glucagon fibril formation indicate that the interaction of the glucagon fibril with lipid bilayers is strongly dependent on the process of fibril formation. A neutral system is thus considered to reflect the fibril formation process in biological cells and provides insight into the mechanism underlying cytotoxicity of glucagon fibrils.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research in an Innovative Area (JP16H00756 to AN) and by Grants-in-Aid for Scientific Research (C) (JP15K06963 to AN) from the Ministry of Culture, Sports, Science and Technology of Japan. The author wishes to thank Izuru Kawamura and Yoshiteru Makino for the discussion on this study and Izumi Yamane, Ayano Momose, Hideki Fujita, Eri Yoshimoto, Akie Kikuchi-Kinoshita, and Kazumi Haya for their experimental assistances.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"glucagon fibril, fibrillation mechanism, two-step autocatalytic reaction, lipid bilayer, solid-state NMR",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71473.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71473.xml",downloadPdfUrl:"/chapter/pdf-download/71473",previewPdfUrl:"/chapter/pdf-preview/71473",totalDownloads:147,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 17th 2019",dateReviewed:"February 10th 2020",datePrePublished:"April 2nd 2020",datePublished:"December 16th 2020",dateFinished:"March 17th 2020",readingETA:"0",abstract:"Glucagon is a 29-amino acid peptide hormone secreted by pancreatic α-cells and interacts with specific receptors located in various organs. Glucagon tends to form gel-like fibril aggregates that are cytotoxic because they activate apoptotic signaling pathways. First, fibril formation by glucagon in acidic solution is discussed in light of morphological and structural changes during elapsed time. Second, we provide kinetic analyses using a two-step autocatalytic reaction mechanism; the first step is a homogeneous nuclear formation process, and the second step is an autocatalytic heterogeneous fibril elongation process. Third, the processes of fibril formation by glucagon in a membrane environment are discussed based on the structural changes in the fibrils. In the presence of bicelles in acidic solution, glucagon interacts with the bicelles and forms fibril intermediates on the bicelle surface and grows into elongated fibrils. Glucagon-dimyristoylphosphatidylcholine (DMPC) bilayers in neutral solution mimic the environment for fibril formation by glucagon under near-physiological condition. Under these conditions, glucagon forms fibril intermediates that grow into elongated fibrils inside the lipid bilayer. Many days after preparing the glucagon-DMPC bilayer sample, the fibrils form networks inside and outside the bilayer. Furthermore, fibril intermediates strongly interact with lipid bilayers to form small particles.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71473",risUrl:"/chapter/ris/71473",signatures:"Akira Naito",book:{id:"10143",title:"Molecular Pharmacology",subtitle:null,fullTitle:"Molecular Pharmacology",slug:"molecular-pharmacology",publishedDate:"December 16th 2020",bookSignature:"Angel Catala and Usama Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10143.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"315504",title:"Emeritus Prof.",name:"Akira",middleName:null,surname:"Naito",fullName:"Akira Naito",slug:"akira-naito",email:"naito@ynu.ac.jp",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Fibril formation by glucagon in acidic solution",level:"1"},{id:"sec_3",title:"3. Cytotoxicity of glucagon fibril",level:"1"},{id:"sec_4",title:"4. Kinetic analysis of the glucagon fibrillation process",level:"1"},{id:"sec_5",title:"5. Fibril formation by glucagon in the presence of bicelles in acidic solution",level:"1"},{id:"sec_6",title:"6. Fibrillation mechanism of glucagon inside the lipid bilayer in the neutral condition",level:"1"},{id:"sec_7",title:"7. Conclusions",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"},{id:"sec_11",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Bromer WW, Sinn LG, Behrens OK. The amino acid sequence of glucagon. V. Location of amide groups, acid degradation studies and summary of sequential evidence. Journal of the American Chemical Society. 1957;79:2807-2810. DOI: 10.1021/ja01568a038'},{id:"B2",body:'Pohl SL, Birnbaumer L, Rodbell M. 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Role of aromatic residues in amyloid fibril formation of human calcitonin by solid-state 13C NMR and molecular dynamics simulation. Physical Chemistry Chemical Physics. 2013;15:8890-8901. DOI: 10.1039/c3cp44544e'},{id:"B16",body:'Itoh-Watanabe H, Kamihira-Ishijima M, Kawamura I, Kondoh M, Nakakoshi M, Sato M, et al. Characterization of the spherical intermediates and fibril formation of hCT in HEPES solution using solid-state 13C-NMR and transmission electron microscopy. Physical Chemistry Chemical Physics. 2013;15:16956-16964. DOI: 10.1039/c3cp52810c'},{id:"B17",body:'Kamgar-Parsi K, Hong L, Naito A, Brooks CL III, Ramamoorthy A. Growth-incompetent monomers of human calcitonin lead to a noncanonical direct relationship between peptide concentration and aggregation lag time. The Journal of Biological Chemistry. 2017;292:14963-14976. DOI: 10.1074/jbcM117.791236'},{id:"B18",body:'Gorman PM, Chakrabartty A. Alzheimer β-amyloid peptides: Structures of amyloid fibrils and alternate aggregation products. Peptide Science. 2001;60:381-394. DOI: 10.1002/1097-0282(2001)60:5<381::AID-BIP/0173>3.0.CO;2-U'},{id:"B19",body:'Tycko R. Insights into the amyloid folding problem from solid-state NMR. Biochemistry. 2003;42:3151-3159. DOI: 10.1021/bi027378p'},{id:"B20",body:'Tycko R. Application of solid state NMR to the structural characterization of amyloid fibrils: Methods and results. Progress in Nuclear Magnetic Resonance Spectroscopy. 2003;42:53-68. DOI: 10.1016/S0079-6565(03)00003-7'},{id:"B21",body:'Petkova AT, Yan W-M, Tycko R. Experimental constraints on quaternary structure in Alzheimer’s β-amyloid fibrils. Biochemistry. 2006;45:498-512. DOI: 10.21/bi051952q'},{id:"B22",body:'Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M, et al. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. 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Journal of Molecular Biology. 2010;397:932-946. DOI: 10.1016/j.jmb.2010.02.012'},{id:"B46",body:'Jong KLD, Incledon B, Yip CM, DeFelippis MR. Amyloid fibrils of glucagon characterized by high-resolution atomic force microscopy. Biophysical Journal. 2006;91:1905-1914. DOI: 10.1529/biophysj.105.077438'},{id:"B47",body:'Saitô H. Conformation-dependent 13C chemical shifts: A new means of conformation characterization as obtained by high-resolution solid-state 13C NMR. Magnetic Resonance in Chemistry. 1986;24:835-852. DOI: 10.1002/mrc.1260241.002'},{id:"B48",body:'Saitô H, Ando I. High-resolution solid-state NMR studies of synthetic and biological macromolecules. Annual Reports on NMR Spectroscopy. 1989;21:209-290. DOI: 10.1016/50066-4103(08)60124-6'},{id:"B49",body:'Saitô H, Ando I, Ramamoorthy A. Chemical shift tensor – The heart of NMR: Insight into biological aspect proteins. Progress in Nuclear Magnetic Resonance Spectroscopy. 2010;57:181-228. 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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+4,800 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+146,150 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
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