Open access peer-reviewed chapter

ADAMTS Proteases: Potential Biomarkers and Novel Therapeutic Targets for Cartilage Health

Written By

Sinan Kandir

Submitted: 13 January 2020 Reviewed: 27 May 2020 Published: 30 June 2020

DOI: 10.5772/intechopen.93046

From the Edited Volume

Equine Science

Edited by Catrin Rutland and Albert Rizvanov

Chapter metrics overview

668 Chapter Downloads

View Full Metrics


The equine locomotor system’s health plays a key role on athletic performance. Bone and joint diseases are the major causes of lameness. Poor performance and diseases lead to great economic loss to equestrian sports and horse breeders. Therefore, prevention, early diagnosis, and therapy of joint diseases are important. A disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) proteinase family plays an important role in many physiological processes such as tissue reorganization, coagulation, and angiogenesis. Aggrecan proteinases ADAMTS-4 and ADAMTS-5 are physiologically responsible for the restructuring with enzymatic cleavage of the cartilage, specific biomarkers in the synovium or body fluids for early diagnosis, and potential specific therapeutic targets in order to their role on degenerative joint diseases physiopathology in humans and various animals.


  • aggrecan
  • equine
  • lameness
  • metalloproteinase
  • proteoglycan

1. Introduction

A disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) protease family plays an important role in many physiological and physiopathological processes. The ADAMTS family is an important potential biomarker for the evaluation of early diagnosis due to its roles in the physiopathological mechanisms of many diseases such as cancer, arthritis, and atherosclerosis. ADAMTS-4 and ADAMTS-5 have been reported to play an important role in the pathogenesis of osteoarthritis in humans and various animals, following their first molecular purification and cloning.

Articular cartilage is structurally composed of partially chondrocyte cells and a large number of extracellular matrix components. Many macromolecules have been identified in cartilage tissue, including collagen fibrils, aggregate proteoglycans, and glycoproteins. Although joint damage is caused by oxidative metabolism-induced free radicals and hypoxic conditions, the main reason is the increase in proteolytic enzymes. Matrix metalloproteinases (MMPs), pro- and anti-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), and retinoic acid are the main biomarkers recommended for the diagnosis of joint damage [1, 2, 3, 4, 5, 6, 7, 8].

In this chapter, we focus on ADAMTS proteases and their role on cartilage health for joints’ stability, their possible usage as damage biomarkers for early diagnosis, and novel therapeutic properties.


2. ADAMTS proteases

Metzincins are a superfamily of zinc-dependent metalloproteases, metalloproteinases, or metalloendopeptidases, which are responsible for many physiological functions that also include cartilage turnover due to their regulatory activities on the extracellular matrix (ECM). The metzincins constitute by the zinc-binding catalytic motif consensus sequence HEXXHXXGXX (H/D) exactly; the binding of a zinc molecule is modulated by the three histidines (or an aspartic acid in the third position), the acid-base catalysis is facilitated by the glutamic acid residue in general, and the steric flexibility is acquired by the small glycine residue in the catalytic motif [9].

The first referenced equine gene mapping project was initiated in October 1995 by the “First International Equine Gene Mapping Workshop,” in order to search answers of the main questions “speed gene” and “evidence of heritable trait”, and the first construction of a low density, male linkage map in 1999 was reported [10, 11]. Thereafter, the first domestic horse gene map (EquCab2.0), a thoroughbred mare Twilight’s gene sequence, was released in 2007 and published in November 2009 [12, 13, 14, 15, 16]. The latest version of high-quality equine gene map EquCab3.0 is available and enables to detailed data about genes and encoding proteins [16]. The Vertebrate Gene Nomenclature Committee (VGNC) [17] has standardized names to genes in vertebrate species including horse [18, 19]. According to these accessible latest data versions, the equine ADAMTS and ADAMTS-like family members with chromosomal locations are listed in Table 1.

Gene/protein nameChromosomal LocationVGNC_IDENSEMBLUniProt
ADAMTS1325(NCBI Gene ID: 100069281)
ADAMTSL1 (Punctin-1)2315075ENSECAG00000015972F6W1K7
ADAMTSL3 (Punctin-2/SH3GL3)122941ENSECAG00000012008F6T6C4
ADAMTSL6 (THSD4)151434ENSECAG00000022944F6UWV1
PAPLN (Papilin)2421150ENSECAT00000008176F6VT48

Table 1.

The equine ADAMTS and ADAMTS-like family members with chromosomal locations and accession numbers.

2.1 ADAMTS family

Towards the end of 1990s, Kuno et al. [20] described a new family of metalloproteinase, which consists of sequence similarity with snake venom disintegrin that was upregulated in colon adenocarcinoma cell line as a specific gene for cachexigenic tumor and was named a disintegrin-like and metalloproteinase with thrombospondin type-1 motif (ADAMTS). The equine ADAMTS and ADAMTS-like proteins are a superfamily comprised of 19 and 7 members, respectively (Table 1). The ADAMTSs are secreted proteinases and multidomain enzymes constituted of zinc-binding active site motif similar to adamalysin (ADAMs) and ensued by a metalloproteinase domain with that of reprolysins (snake venom metalloproteinases) and disintegrin-like domain (Figures 1 and 3). ADAMTS-like (ADAMTSL) family and papilin are newly identified and secreted ECM-related proteins which are relatives to ADAMTS proteases. Additionally, they lack catalytic activity due to the absence of prometalloprotease and the disintegrin-like domain which are found in the ADAMTSs [21, 22, 23, 24]. ADAMTSs differ from ADAMs with the lack of a transmembrane domain and the inclusion of well-conserved thrombospondin 1-like repeats, a cysteine-rich domain, and the CUB (complement subcomponents C1s/C1r, Uegf, BMP1) domain, thus being soluble extracellular proteases [25, 26, 27, 28, 29, 30, 31].

Figure 1.

Phylogenetic analysis of equine ADAMTS protein family. The evolutionary history was inferred using the maximum parsimony method. The most parsimonious tree with length = 9505 is shown. The consistency index is (0.751174), the retention index is (0.551189), and the composite index is 0.440603 (0.414039) for all sites and parsimony-informative sites. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (500 replicates) is shown next to the branches [43]. The MP tree was obtained using the subtree-pruning-regrafting (SPR) algorithm (p. 126 in Ref. [44]) with search level 1 in which the initial trees were obtained by the random addition of sequences (10 replicates). Branch lengths were calculated using the average pathway method (see p. 132 in Ref. [2]) and are in the units of the number of changes over the whole sequence. They are shown next to the branches. This analysis involved 19 amino acid sequences. There were a total of 2768 positions in the final dataset. Evolutionary analyses were conducted in MEGA X [45].

The main physiological functions of equine ADAMTSLs and papilin are extensively unknown; thus they have some troubles and need to further detailed investigations. However, recent studies on genome-wide association analysis and transgenic animals have indicated that ADAMTS, ADAMTSL, and papilin gene mutations cause lethal embryonic defects and autosomal recessive Mendelian disorders such as human Ehlers-Danlos syndrome [32], bovine dermatosparaxis [33, 34], human Weill-Marchesani syndrome [35], canine ectopia lentis [36], human Geleophysic dysplasia [37], canine Musladin-Lueke syndrome [38], and thrombotic thrombocytopenic purpura [39]. In consideration of this knowledge, ADAMTSs, ADAMTSLs, and papilin could be responsible as most commonly screened genetic disorders among horses as early embryonic death and abnormalities, junctional epidermolysis bullosa [40], hereditary equine regional dermal asthenia [41], thrombocytopenia and, von Willebrand disease [42].


3. Role of ADAMTS family on equine cartilage health

Musculoskeletal system health is crucial for equine locomotion. This system is responsible to deploy the mechanical energy to the joints for efficient movement and specific biomechanical functions. There are many types of joints presented, where a majority of the free movements are managed by diarthrodial or synovial joints in the body. Cartilage tissue, which is the most important part of the diarthrodial joints, is absorbed and the loading energy throughout locomotion is distributed. Alterations due to inaccurately loading or metabolic disruptions could lead to acute or chronic damage, namely as arthritis, osteoarthrosis, or osteoarthritis to the joint and its critical component cartilage tissue, and restrict the locomotor functions. It is important to understand the molecular mechanisms of healthy and damaged cartilage tissues by the novel candidate molecular biomarkers in order to early detection, easily clinical application, and therapy. Hence, we will focus on the cartilage health and importance of the ADAMTS family in this section.

3.1 Healthy cartilage tissue

Cartilages are divided into three major types as histological and biochemical properties in the body as hyaline, elastic and fibrocartilage. The distinctive features among these cartilage types are water content/dry matter balance and fiber types. In the diarthrodial joints, hyaline cartilage is existed on the articular surfaces and is well resist to pressure stress during various locomotion by its unique structure [46, 47].

Avascularized, unnerved, alymphatic hyaline cartilage (Latin words “hyălĭnus” meaning “glassy; made of glass; transparent”) tissue’s matrix is fundamentally constituted by water (%63–70), collagens (the majority type II in normal hyaline cartilage), non-collagenous proteins, and proteoglycans (the majority of aggrecans), while the most compounds are glycosaminoglycans (GAG) [48, 49].

Proteoglycans are classified into four subgroups related to their function: intracellular, cell-surface, pericellular, and extracellular. In the cartilage tissue, hyaluronan- and lectin-binding proteoglycans (hyalectans; aggrecan, versican, neurocan, and brevican) and small leucine-rich proteoglycans exist. Hyalectans are compromised with a similar structure in their tridomain structure; the N-terminal domain binds to hyaluronan, a central domain with the core protein for attachment of GAG chains, and the C-terminal region that binds lectins [50, 51].

The major proteoglycans in the diarthrodial joints aggrecans are the crucial elements for the biomechanical function with well-balanced load distribution and transmissions in order to provide the viscoelastic properties, the tight junctions, and the bridges of the extracellular matrix (ECM) [50, 52, 53, 54, 55]. Aggrecans have a large molecular mass that contains GAG side chains comprising of the mostly chondroitin sulfate and keratan sulfate. They have three globular domains (G1, G2, and G3) to maintain the stabilization of protein complexes and to ensure mechanical features of cartilage. These highly conserved globular domains among the vertebrates have specific cleavage sites for proteases such as ADAMTSs (Figure 2) [50, 55, 56, 57]. The GAG’s chondroitin sulfate and keratan sulfate contents of aggrecan could directly affect the aggrecanase activity by ADAMTSs [58].

Figure 2.

Schematic view of aggrecan proteoglycan [50, 55, 56].

Although, the hyaline cartilage consists of the chondrocytes which are the only cell type; this cell population has shown different morphological properties under the microscope and has been identified as dark, light, and adipocyte-like (adipochondrocytes) [59]. Chondrocytes manage the functional regulation of joint. These cell groups provide the synthesis and degradation of the ECM compnents, to support growth and regeneration, through the maintenance the gene expression and metabolism responded by mechanical stimuli. Extracellular matrix and proteoglycans are expressed by chondrocytes in articular joints [60, 61, 62, 63, 64].

The interleukins (ILs) and tumor necrosis factor α (TNF-α) cytokines are synthesized by chondrocytes, synovium, or inflammatory cells [7, 65]. Proteoglycan depletion has been stimulating physiopathologic processes, which is the main cause of degenerative joint diseases, e.g., osteoarthritis [66, 67]. Interleukins and TNF-α exert their effects on many diseases nonselectively from dental to cancer [68, 69], despite that a biomarker must be tissue-specific [70, 71]. Thus, in the last decade, the equine orthopedic researches have been deeply focused on proteoglycans, especially aggrecanases.

3.2 Aggrecanases on cartilage physiopathology

As it is well known, the proteases are responsible for proteolysis processes, which are catalytic enzymes to breakdown of the proteins into small polypeptides and amino acids by cleaved peptide bonds. The metalloproteinase superfamily members show their proteinase activity on osteoarthritis formation throughout the physiopathological processes. The matrix metalloproteinases (MMPs) and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) are extensively studied; besides this, recent advances have indicated that the role of ADAMTS proteinase family is more considerable due to its abundant and specific aggrecanase activity by ADAMTS-4 and -5.

The aggrecan residues which cleaved at the glutamate 373-alanine 374 bond between the G1 and G2 interglobular domains were found at the synovial fluid analysis from various joint diseases (inflammatory or noninflammatory) in humans [72]. The first aggrecanase was purified and cloned by Tortorella and named as aggrecanase-1 (currently termed as ADAMTS-4). They showed that ADAMTS-4 cleaves the aggrecan at the glutamic acid-373-alanine-374 bond [73]. After a while, Abbaszade et al. described aggrecanase-2 and named ADAMTS-11 (presently known as ADAMTS-5) [74]. ADAMTS-4 and ADAMTS-5 cleave the aggrecan at five common aggrecanase specific sites (Glu373-Ala374, Glu1480-Gly1481, Glu1667-Gly1668, Glu1771-Ala1772, and Glu1871-Leu1872,); nonetheless, ADAMTS-5 cleaves an additional site (Glu1480-Gly1481). Moreover, ADAMTS-5 is approximately twice slower than ADAMTS-4 [75, 76].

ADAMTS-4 and -5 are distributed in equine hoof lamina [78] and joints [79] and are expressed more in cartilage tissue than other tissues [80]. In our study, we observed concour horses after 50 minutes of a regular exercise program. As a result the serum ADAMTS-5 levels significantly increased but ADAMTS-4 did not. We concluded that ADAMTS-4 and ADAMTS-5 are using different pathways to physiologic and physiopathologic response [81]. Additionally and interestingly, the owners, whose horses had higher individual ADAMTS-5 serum levels, called the local veterinarians to complain about an orthopedic problem two or three weeks after our observations (unpublished data).

ADAMTS-4 needs to interact with sulfated GAGs that are attached to aggrecan core protein in order to effectively aggrecan degradation [58, 82]. ADAMTS-4 lacks the thrombospondin repeat domain on C-terminal region (Figure 3). This unique configuration allows bind to the adhesive glycoprotein fibronectin [82, 83]. Fibronectin is a glycoprotein that is found in low levels under physiologic conditions at the articular surface of cartilage and increases on pathologic conditions by activating innate immune response with toll-like receptors that are responded to regulate the innate immune system in case of pathogen-related inflammation [84, 85]. Hashimoto et al. reported that fibronectin is a novel inhibitor of ADAMTS4 activity in addition to its original endogenous inhibitor TIMP-3. Hence, fibronectin could be a potent preventive therapeutic against aggrecan degradation related to degenerative joint diseases [82]. While ADAMTS-4 is mediated by TNF-α, IL-1β, and nuclear factor-kappa B (NFκB) released from synovial macrophages, the regulation of ADAMTS-5 is not totally but predominantly independent of the these cytokine response [86].

Figure 3.

Domain organization of ADAMTS aggrecanases. SP: signal peptide; T: thrombospondin type 1 motif; and CYS: cysteine [77].


4. Conclusion

The differences between synthesis pathways of ADAMTS-4 and ADAMTS-5 have to be taken into consideration on the TNF-α and IL-1 neutralization-targeted cytokine inhibitor therapies throughout degenerative joint diseases. In addition to classical therapy strategies, novel gene therapies are arising nowadays. An exciting work on this subject is a knockout murine model by the correction of ADAMTS-13 gene, which causes von Willebrand disease and leads to thrombotic thrombocytopenic purpura [87]. Transgenic animal studies with ADAMTS-4 and -5 double knockout mice [88, 89] revealed that aggrecan deletion protects from progressive osteoarthritis. These results have indicated that ADAMTS-4 and -5 may be potent therapeutic agents against laminitis and osteoarthritis, tendon, and ligament injuries for equine gene therapy.



Special thanks to Fulya Kandır for her patience and support during the writing process, Cemil Erdem (Cearts Creative Agency) for drawing the Figure 3 and Mac Hamidou Camara for his support.


  1. 1. McIlwraith CW. Use of synovial fluid and serum biomarkers in equine bone and joint disease: A review. Equine Veterinary Journal. 2005;37(5):473-482. PubMed PMID: 16163952. [Epub: 17 September 2005]
  2. 2. Brama PA, van den Boom R, DeGroott J, Kiers GH, van Weeren PR. Collagenase-1 (MMP-1) activity in equine synovial fluid: Influence of age, joint pathology, exercise and repeated arthrocentesis. Equine Veterinary Journal. 2004;36(1):34-40. PubMed PMID: 14756369. [Epub: 06 February 2004]
  3. 3. Donabedian M, van Weeren PR, Perona G, Fleurance G, Robert C, Leger S, et al. Early changes in biomarkers of skeletal metabolism and their association to the occurrence of osteochondrosis (OC) in the horse. Equine Veterinary Journal. 2008;40(3):253-259. PubMed PMID: 18267892. [Epub: 13 February 2008]
  4. 4. Frisbie DD, Al-Sobayil F, Billinghurst RC, Kawcak CE, McIlwraith CW. Changes in synovial fluid and serum biomarkers with exercise and early osteoarthritis in horses. Osteoarthritis and Cartilage. 2008;16(10):1196-1204. PubMed PMID: 18442931. [Epub: 30 April 2008]
  5. 5. Davies MR, Ribeiro LR, Downey-Jones M, Needham MR, Oakley C, Wardale J. Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint. Arthritis and Rheumatism. 2009;60(6):1722-1732. PubMed PMID: 19479829. [Epub: 30 May 2009]
  6. 6. Legrand CB, Lambert CJ, Comblain FV, Sanchez C, Henrotin YE. Review of soluble biomarkers of osteoarthritis: Lessons from animal models. Cartilage. 2017;8(3):211-233. PubMed PMID: 28618869. PMCID: PMC5625856. [Epub: 18 June 2017]
  7. 7. Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators of Inflammation. 2014;2014:561459. PubMed PMID: 24876674. PMCID: PMC4021678. [Epub: 31 May 2014]
  8. 8. Von den Hoff HW, van Kampen GP, van der Korst JK. Proteoglycan depletion of intact articular cartilage by retinoic acid is irreversible and involves loss of hyaluronate. Osteoarthritis and Cartilage. 1993;1(3):157-166. PubMed PMID: 15449421. [Epub: 01 July 1993]
  9. 9. Brunet FG, Fraser FW, Binder MJ, Smith AD, Kintakas C, Dancevic CM, et al. The evolutionary conservation of the A disintegrin-like and metalloproteinase domain with Thrombospondin-1 motif metzincins across vertebrate species and their expression in teleost zebrafish. BMC Evolutionary Biology. 2015;15:22. PubMed PMID: 25879701. PMCID: PMC4349717. [Epub: 17 April 2015]
  10. 10. Modern Horse Breeding, Inc. First International Equine Gene Mapping Workshop [Internet]. Lexington, Ky: Modern Horse Breeding, Inc; 1995. Available from: [cited 20 February 2020]
  11. 11. Guerin G, Bailey E, Bernoco D, Anderson I, Antczak DF, Bell K, et al. Report of the international equine gene mapping workshop: Male linkage map. Animal Genetics. 1999;30(5):341-354. PubMed PMID: 10582279. [Epub: 03 December 1999]
  12. 12. Raudsepp T, Finno CJ, Bellone RR, Petersen JL. Ten years of the horse reference genome: Insights into equine biology, domestication and population dynamics in the post-genome era. Animal Genetics. 2019;50(6):569-597. PubMed PMID: 31568563. PMCID: PMC6825885. [Epub: 01 October 2019]
  13. 13. Finno CJ, Bannasch DL. Applied equine genetics. Equine Veterinary Journal. 2014;46(5):538-544. PubMed PMID: 24802051. PMCID: PMC4327934. [Epub: 08 May 2014]
  14. 14. Brosnahan MM, Brooks SA, Antczak DF. Equine clinical genomics: A clinician’s primer. Equine Veterinary Journal. 2010;42(7):658-670. PubMed PMID: 20840582. PMCID: PMC3297474. [Epub: 16 September 2010]
  15. 15. Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F, et al. Genome sequence, comparative analysis, and population genetics of the domestic horse. Science. 2009;326(5954):865-867. PubMed PMID: 19892987. PMCID: PMC3785132. [Epub: 07 November 2009]
  16. 16. Kalbfleisch TS, Rice ES, DePriest MS Jr, Walenz BP, Hestand MS, Vermeesch JR, et al. Improved reference genome for the domestic horse increases assembly contiguity and composition. Communications Biology. 2018;1:197. PubMed PMID: 30456315. PMCID: PMC6240028 adviser of Dovetail Genomics, LLC. The other authors declare no competing interests. [Epub: 21 November 2018]
  17. 17. Braschi B, Denny P, Gray K, Jones T, Seal R, Tweedie S, et al. The HGNC and VGNC resources in 2019. Nucleic Acids Research. 2019;47(D1):D786-DD92. PubMed PMID: 30304474. PMCID: PMC6324057. [Epub: 12 October 2018]
  18. 18. Cunningham F, Achuthan P, Akanni W, Allen J, Amode MR, Armean IM, et al. Ensembl 2019. Nucleic Acids Research. 2019;47(D1):D745-DD51. PubMed PMID: 30407521. PMCID: PMC6323964. [Epub: 09 November 2018]
  19. 19. Hestand MS, Kalbfleisch TS, Coleman SJ, Zeng Z, Liu J, Orlando L, et al. Annotation of the protein coding regions of the equine genome. PLoS One. 2015;10(6):e0124375. PubMed PMID: 26107351. PMCID: PMC4481266. [Epub: 25 June 2015]
  20. 20. Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K. Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. The Journal of Biological Chemistry. 1997;272(1):556-562. PubMed PMID: 8995297. [Epub: 03 January 1997]
  21. 21. Fessler JH, Kramerova I, Kramerov A, Chen Y, Fessler LI. Papilin, a novel component of basement membranes, in relation to ADAMTS metalloproteases and ECM development. The International Journal of Biochemistry & Cell Biology. 2004;36(6):1079-1084. PubMed PMID: 15094122. [Epub: 20 April 2004]
  22. 22. Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics. Matrix Biology. 2015;44-46:24-37. PubMed PMID: 25770910. [Epub: 17 March 2015]
  23. 23. Hirohata S, Wang LW, Miyagi M, Yan L, Seldin MF, Keene DR, et al. Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix. The Journal of Biological Chemistry. 2002;277(14):12182-12189. PubMed PMID: 11805097. [Epub: 24 January 2002]
  24. 24. Kramerova IA, Kawaguchi N, Fessler LI, Nelson RE, Chen Y, Kramerov AA, et al. Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases. Development. 2000;127(24):5475-5485. PubMed PMID: 11076767. [Epub: 15 November 2000]
  25. 25. Cerda-Costa N, Gomis-Ruth FX. Architecture and function of metallopeptidase catalytic domains. Protein Science. 2014;23(2):123-144. PubMed PMID: 24596965. PMCID: PMC3926739. [Epub: 07 March 2014]
  26. 26. Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, et al. Crystal structure and substrate-induced activation of ADAMTS13. Nature Communications. 2019;10(1):3781. PubMed PMID: 31439947. PMCID: PMC6706451. [Epub: 24 August 2019]
  27. 27. Bork P, Beckmann G. The CUB domain. A widespread module in developmentally regulated proteins. Journal of Molecular Biology. 1993;231(2):539-545. PubMed PMID: 8510165. [Epub: 20 May 1993]
  28. 28. Jones GC, Riley GP. ADAMTS proteinases: A multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis. Arthritis Research & Therapy. 2005;7(4):160-169. PubMed PMID: 15987500. PMCID: PMC1175049. [Epub: 01 July 2005]
  29. 29. van Goor H, Melenhorst WB, Turner AJ, Holgate ST. Adamalysins in biology and disease. The Journal of Pathology. 2009;219(3):277-286. PubMed PMID: 19662664. [Epub: 08 August 2009]
  30. 30. Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lopez-Otin C. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene. 2002;283(1-2):49-62. PubMed PMID: 11867212. [Epub: 28 February 2002]
  31. 31. Tang BL, Hong W. ADAMTS: A novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats. FEBS Letters. 1999;445(2-3):223-225. PubMed PMID: 10094461. [Epub: 27 March 1999]
  32. 32. Colige A, Nuytinck L, Hausser I, van Essen AJ, Thiry M, Herens C, et al. Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (type VIIC) and common polymorphisms in the ADAMTS2 gene. The Journal of Investigative Dermatology. 2004;123(4):656-663. PubMed PMID: 15373769. [Epub: 18 September 2004]
  33. 33. Carty CI, Lee AM, Wienandt NA, Stevens EL, Alves DA, Browne JA, et al. Dermatosparaxis in two limousin calves. Irish Veterinary Journal. 2016;69:15. PubMed PMID: 27777746. PMCID: PMC5070005. [Epub: 26 November 2016]
  34. 34. Colige A, Sieron AL, Li SW, Schwarze U, Petty E, Wertelecki W, et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. American Journal of Human Genetics. 1999;65(2):308-317. PubMed PMID: 10417273. PMCID: PMC1377929. [Epub: 27 July 1999]
  35. 35. Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Megarbane A, Alswaid A, et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. American Journal of Human Genetics. 2004;75(5):801-806. PubMed PMID: 15368195. PMCID: PMC1182109. [Epub: 16 September 2004]
  36. 36. Farias FH, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, et al. An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Investigative Ophthalmology & Visual Science. 2010;51(9):4716-4721. PubMed PMID: 20375329. [Epub: 09 April 2010]
  37. 37. Allali S, Le Goff C, Pressac-Diebold I, Pfennig G, Mahaut C, Dagoneau N, et al. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. Journal of Medical Genetics. 2011;48(6):417-421. PubMed PMID: 21415077. PMCID: PMC4413937. [Epub: 19 March 2011]
  38. 38. Bader HL, Ruhe AL, Wang LW, Wong AK, Walsh KF, Packer RA, et al. An ADAMTSL2 founder mutation causes Musladin-Lueke syndrome, a heritable disorder of beagle dogs, featuring stiff skin and joint contractures. PLoS One. 2010;5(9):e12817. PubMed PMID: 20862248. PMCID: PMC2941456. [Epub: 24 September 2010]
  39. 39. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annual Review of Medicine. 2015;66:211-225. PubMed PMID: 25587650. PMCID: PMC4599565. [Epub: 15 January 2015]
  40. 40. Graves KT, Henney PJ, Ennis RB. Partial deletion of the LAMA3 gene is responsible for hereditary junctional epidermolysis bullosa in the American Saddlebred horse. Animal Genetics. 2009;40(1):35-41. PubMed PMID: 19016681. [Epub: 20 November 2008]
  41. 41. White SD, Affolter VK, Bannasch DL, Schultheiss PC, Hamar DW, Chapman PL, et al. Hereditary equine regional dermal asthenia (“hyperelastosis cutis”) in 50 horses: Clinical, histological, immunohistological and ultrastructural findings. Veterinary Dermatology. 2004;15(4):207-217. PubMed PMID: 15305927. [Epub: 13 August 2004]
  42. 42. Rathgeber RA, Brooks MB, Bain FT, Byars TD. Clinical vignette. Von Willebrand disease in a thoroughbred mare and foal. Journal of Veterinary Internal Medicine. 2001;15(1):63-66. PubMed PMID: 11215915. [Epub: 24 February 2001]
  43. 43. Felsenstein J. Confidence limits on phylogenies: An approach using the bootstrap. Evolution. 1985;39(4):783-791. PubMed PMID: 28561359. [Epub: 01 July 1985]
  44. 44. Nei M, Kumar S. Molecular Evolution and Phylogenetics. Oxford, New York: Oxford University Press; 2000. xiv, p. 333
  45. 45. Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: Molecular evolutionary genetics analysis across computing platforms. Molecular Biology and Evolution. 2018;35(6):1547-1549. PubMed PMID: 29722887. PMCID: PMC5967553. [Epub: 04 July 2018]
  46. 46. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: Structure, composition, and function. Sports Health. 2009;1(6):461-468. PubMed PMID: 23015907. PMCID: PMC3445147. [Epub: 01 November 2009]
  47. 47. Hall BK. Bones and Cartilage : Developmental and Evolutionary Skeletal Biology. Amsterdam/London: Elsevier Academic; 2005
  48. 48. Seibel MJ, Robins SP, Bilezikian JP. Dynamics of Bone and Cartilage Metabolism. 2nd ed. United States of America: Academic Press; 2006
  49. 49. Smith DW, Gardiner BS, Zhang L, Grodzinsky AJ. Articular Cartilage Dynamics. Berlin, Heidelberg, New York, NY: Springer; 2018
  50. 50. Iozzo RV, Schaefer L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. Matrix Biology. 2015;42:11-55. PubMed PMID: 25701227. PMCID: PMC4859157. [Epub: 24 February 2015]
  51. 51. Kjellen L, Lindahl U. Proteoglycans: Structures and interactions. Annual Review of Biochemistry. 1991;60:443-475. PubMed PMID: 1883201. [Epub: 01 January 1991]
  52. 52. Murray RC, Birch HL, Lakhani K, Goodship AE. Biochemical composition of equine carpal articular cartilage is influenced by short-term exercise in a site-specific manner. Osteoarthritis and Cartilage. 2001;9(7):625-632. PubMed PMID: 11597175. [Epub: 13 October 2001]
  53. 53. Viitanen M, Bird J, Smith R, Tulamo RM, May SA. Biochemical characterisation of navicular hyaline cartilage, navicular fibrocartilage and the deep digital flexor tendon in horses with navicular disease. Research in Veterinary Science. 2003;75(2):113-120. PubMed PMID: 12893159. [Epub: 02 August 2003]
  54. 54. Nugent GE, Law AW, Wong EG, Temple MM, Bae WC, Chen AC, et al. Site- and exercise-related variation in structure and function of cartilage from equine distal metacarpal condyle. Osteoarthritis and Cartilage. 2004;12(10):826-833. PubMed PMID: 15450533. [Epub: 29 September 2004]
  55. 55. Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB. Structure and function of aggrecan. Cell Research. 2002;12(1):19-32. PubMed PMID: 11942407. [Epub: 11 April 2002]
  56. 56. Caporali EH, Kuykendall T, Stewart MC. Complete sequencing and characterization of equine aggrecan. Veterinary and Comparative Orthopaedics and Traumatology. 2015;28(2):79-87. PubMed PMID: 25632964. [Epub: 31 January 2015]
  57. 57. Aspberg A. The different roles of aggrecan interaction domains. The Journal of Histochemistry and Cytochemistry. 2012;60(12):987-996. PubMed PMID: 23019016. PMCID: PMC3527881. [Epub: 29 September 2012]
  58. 58. Pratta MA, Tortorella MD, Arner EC. Age-related changes in aggrecan glycosylation affect cleavage by aggrecanase. The Journal of Biological Chemistry. 2000;275(50):39096-39102. PubMed PMID: 10991945. [Epub: 19 September 2000]
  59. 59. Ahmed Y. Chondrocyte heterogeneity; it is the time to update the understanding of cartilage histology. SVU-International Journal of Veterinary Sciences. 2018;1(2):1-3
  60. 60. Hall AC. The role of chondrocyte morphology and volume in controlling phenotype-implications for osteoarthritis, cartilage repair, and cartilage engineering. Current Rheumatology Reports. 2019;21(8):38. PubMed PMID: 31203465. PMCID: PMC6571082. [Epub: 17 June 2019]
  61. 61. Hall AC, Bush PG, Davidson ME, Kempson SA. Equine articular cartilage chondrocytes: Opening the black box. Equine Veterinary Journal. 2003;35(5):425-428. PubMed PMID: 12875317. [Epub: 24 July 2003]
  62. 62. Wilkins RJ, Browning JA, Ellory JC. Surviving in a matrix: Membrane transport in articular chondrocytes. The Journal of Membrane Biology. 2000;177(2):95-108. PubMed PMID: 11003684. [Epub: 26 September 2000]
  63. 63. Mobasheri A, Matta C, Uzieliene I, Budd E, Martin-Vasallo P, Bernotiene E. The chondrocyte channelome: A narrative review. Joint, Bone, Spine. 2019;86(1):29-35. PubMed PMID: 29452304. [Epub: 17 February 2018]
  64. 64. O’Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(4):1316-1321. PubMed PMID: 24474754. PMCID: PMC3910592. [Epub: 30 January 2014]
  65. 65. Beutler BA. The role of tumor necrosis factor in health and disease. The Journal of Rheumatology. Supplement. 1999;57:16-21. PubMed PMID: 10328138. [Epub: 18 May 1999]
  66. 66. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. OSteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism. 2012;64(6):1697-1707. PubMed PMID: 22392533. PMCID: PMC3366018. [Epub: 07 March 2012]
  67. 67. Malemud CJ. Changes in proteoglycans in osteoarthritis: Biochemistry, ultrastructure and biosynthetic processing. The Journal of Rheumatology. Supplement. 1991;27:60-62. PubMed PMID: 2027133. [Epub: 01 February 1991]
  68. 68. Idris A, Ghazali NB, Koh D. Interleukin 1beta-A potential salivary biomarker for cancer progression? Biomark Cancer. 2015;7:25-29. PubMed PMID: 26244033. PMCID: PMC4498652. [Epub: 06 August 2015]
  69. 69. Gomes FI, Aragao MG, Barbosa FC, Bezerra MM, de Paulo Teixeira Pinto V, Chaves HV. Inflammatory cytokines interleukin-1beta and tumour necrosis factor-alpha—Novel biomarkers for the detection of periodontal diseases: A literature review. Journal of Oral & Maxillofacial Research. 2016;7(2):e2. PubMed PMID: 27489606. PMCID: PMC4970502. [Epub: 05 August 2016]
  70. 70. Strimbu K, Tavel JA. What are biomarkers? Current Opinion in HIV and AIDS. 2010;5(6):463-466. PubMed PMID: 20978388. PMCID: PMC3078627. [Epub: 28 October 2010]
  71. 71. McIlwraith CW, Kawcak CE, Frisbie DD, Little CB, Clegg PD, Peffers MJ, et al. Biomarkers for equine joint injury and osteoarthritis. Journal of Orthopaedic Research. 2018;36(3):823-831. PubMed PMID: 28921609. [Epub: 19 September 2017]
  72. 72. Lohmander LS, Neame PJ, Sandy JD. The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. Arthritis and Rheumatism. 1993;36(9):1214-1222. PubMed PMID: 8216415. [Epub: 01 September 1993]
  73. 73. Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R, et al. Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins. Science. 1999;284(5420):1664-1666. PubMed PMID: 10356395. [Epub: 05 June 1999]
  74. 74. Abbaszade I, Liu RQ , Yang F, Rosenfeld SA, Ross OH, Link JR, et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. The Journal of Biological Chemistry. 1999;274(33):23443-23450. PubMed PMID: 10438522. [Epub: 07 August 1999]
  75. 75. Fosang AJ, Rogerson FM, East CJ, Stanton H. ADAMTS-5: The story so far. European Cells & Materials. 2008;15:11-26. PubMed PMID: 18247274. [Epub: 06 February 2008]
  76. 76. Tortorella MD, Liu RQ , Burn T, Newton RC, Arner E. Characterization of human aggrecanase 2 (ADAM-TS5): Substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biology. 2002;21(6):499-511. PubMed PMID: 12392761. [Epub: 24 October 2002]
  77. 77. Nagase H, Kashiwagi M. Aggrecanases and cartilage matrix degradation. Arthritis Research & Therapy. 2003;5(2):94-103. PubMed PMID: 12718749. PMCID: PMC165039. [Epub: 30 April 2003]
  78. 78. Pawlak E, Wang L, Johnson PJ, Nuovo G, Taye A, Belknap JK, et al. Distribution and processing of a disintegrin and metalloproteinase with thrombospondin motifs-4, aggrecan, versican, and hyaluronan in equine digital laminae. American Journal of Veterinary Research. 2012;73(7):1035-1046. PubMed PMID: 22738056. PMCID: PMC3535468. [Epub: 29 June 2012]
  79. 79. Peffers MJ, Thornton DJ, Clegg PD. Characterization of neopeptides in equine articular cartilage degradation. Journal of Orthopaedic Research. 2016;34(1):106-120. PubMed PMID: 26124002. PMCID: PMC4737130. [Epub: 01 July 2015]
  80. 80. Moon J-W, Ahn K, Bae J-H, Nam G-H, Cho B-W, Park K-D, et al. mRNA sequence analysis and quantitative expression of the ADAMTS4 gene in the thoroughbred horse. Genes & Genomics. 2012;34(4):441-445
  81. 81. Kandir S, Tekin G, Er C, Karakurt S. Effects of exercise on ADAMTS-4 and ADAMTS-5 levels in sport horses. Acta Physiologica. 2017;221:194-194. PubMed PMID: WOS:000408842000350. English
  82. 82. Hashimoto G, Shimoda M, Okada Y. ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. The Journal of Biological Chemistry. 2004;279(31):32483-32491. PubMed PMID: 15161923. [Epub: 27 May 2004]
  83. 83. Tortorella M, Pratta M, Liu RQ , Abbaszade I, Ross H, Burn T, et al. The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. The Journal of Biological Chemistry. 2000;275(33):25791-25797. PubMed PMID: 10827174. [Epub: 29 May 2000]
  84. 84. Klein RM, Zheng M, Ambesi A, Van De Water L, McKeown-Longo PJ. Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin. Journal of Cell Science. 2003;116(Pt 22):4663-4674. PubMed PMID: 14576359. [Epub: 25 October 2003]
  85. 85. Kelsh R, You R, Horzempa C, Zheng M, McKeown-Longo PJ. Regulation of the innate immune response by fibronectin: Synergism between the III-1 and EDA domains. PLoS One. 2014;9(7):e102974. PubMed PMID: 25051083. PMCID: PMC4106844. [Epub: 23 July 2014]
  86. 86. Bondeson J, Wainwright S, Hughes C, Caterson B. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: A review. Clinical and Experimental Rheumatology. 2008;26(1):139-145. PubMed PMID: 18328163. eng
  87. 87. Laje P, Shang D, Cao W, Niiya M, Endo M, Radu A, et al. Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy. Blood. 2009;113(10):2172-2180. PubMed PMID: 19141866. PMCID: PMC2652365. [Epub: 15 January 2009]
  88. 88. Majumdar MK, Askew R, Schelling S, Stedman N, Blanchet T, Hopkins B, et al. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis and Rheumatism. 2007;56(11):3670-3674. PubMed PMID: 17968948. [Epub: 31 October 2007]
  89. 89. Ilic MZ, East CJ, Rogerson FM, Fosang AJ, Handley CJ. Distinguishing aggrecan loss from aggrecan proteolysis in ADAMTS-4 and ADAMTS-5 single and double deficient mice. The Journal of Biological Chemistry. 2007;282(52):37420-37428. PubMed PMID: 17938173. [Epub: 17 October 2007]

Written By

Sinan Kandir

Submitted: 13 January 2020 Reviewed: 27 May 2020 Published: 30 June 2020