procollagen n endopeptidase


Summary: An extracellular endopeptidase which excises a block of peptides at the amino terminal, nonhelical region of the procollagen molecule with the formation of collagen. Absence or deficiency of the enzyme causes accumulation of procollagen which results in the inherited connective tissue disorder--dermatosparaxis. EC

Top Publications

  1. Westling J, Fosang A, Last K, Thompson V, Tomkinson K, Hebert T, et al. ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain. J Biol Chem. 2002;277:16059-66 pubmed
    ..These results show that G1-VDIPEN(341) is a product of both MMP and ADAMTS4 activities and challenge the widely held assumption that this product represents a specific indicator of MMP- or cathepsin B-mediated aggrecan degradation. ..
  2. Patwari P, Gao G, Lee J, Grodzinsky A, Sandy J. Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage. Osteoarthritis Cartilage. 2005;13:269-77 pubmed
  3. Hamel M, Mayer J, Gottschall P. Altered production and proteolytic processing of brevican by transforming growth factor beta in cultured astrocytes. J Neurochem. 2005;93:1533-41 pubmed
    ..Thus, TGFbeta may play a role in neuronal plasticity through its regulation of brevican and the activity of the ADAMTSs. ..
  4. Tang B. ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol. 2001;33:33-44 pubmed
    ..Current and future studies on this emerging group of ECM proteases may provide important insights into developmental or pathological processes involving ECM remodeling. ..
  5. Tsuzaki M, Guyton G, Garrett W, Archambault J, Herzog W, Almekinders L, et al. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res. 2003;21:256-64 pubmed
    ..Endogenous IL-1 beta might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix. ..
  6. Westling J, Gottschall P, Thompson V, Cockburn A, Perides G, Zimmermann D, et al. ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein. Biochem J. 2004;377:787-95 pubmed
  7. Moulharat N, Lesur C, Thomas M, Rolland Valognes G, Pastoureau P, Anract P, et al. Effects of transforming growth factor-beta on aggrecanase production and proteoglycan degradation by human chondrocytes in vitro. Osteoarthritis Cartilage. 2004;12:296-305 pubmed
    ..It is, therefore, proposed that the role of TGFbeta in cartilage matrix turnover is not limited to anabolic and anti-catabolic actions, but also extends to selective degradation of matrix components such as aggrecan. ..
  8. Malfait A, Liu R, Ijiri K, Komiya S, Tortorella M. Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem. 2002;277:22201-8 pubmed
    ..These results suggest that ADAM-TS4 and ADAM-TS5 represent a potential target for the treatment of osteoarthritis. ..
  9. Yamanishi Y, Boyle D, Clark M, Maki R, Tortorella M, Arner E, et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. J Immunol. 2002;168:1405-12 pubmed
    ..In contrast, aggrecanase-2 protein may be regulated by a post-translational mechanism in OA and RA ST. Synovial and FLS production of aggrecanase can contribute to cartilage degradation in RA and OA. ..

More Information


  1. Yuan W, Matthews R, Sandy J, Gottschall P. Association between protease-specific proteolytic cleavage of brevican and synaptic loss in the dentate gyrus of kainate-treated rats. Neuroscience. 2002;114:1091-101 pubmed
    ..The observed ADAMTS-induced cleavage of brevican in the dentate outer molecular layer is closely associated with diminished synaptic density, and may, therefore, contribute to synaptic loss and/or reorganization in this region. ..
  2. Bau B, Gebhard P, Haag J, Knorr T, Bartnik E, Aigner T. Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum. 2002;46:2648-57 pubmed
  3. Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem. 2001;276:12501-4 pubmed
    ..This provides a starting point for developing a biologically available aggrecanase inhibitor suitable for the treatment of arthritis. ..
  4. Hashimoto G, Shimoda M, Okada Y. ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. J Biol Chem. 2004;279:32483-91 pubmed
  5. Colige A, Beschin A, Samyn B, Goebels Y, Van Beeumen J, Nusgens B, et al. Characterization and partial amino acid sequencing of a 107-kDa procollagen I N-proteinase purified by affinity chromatography on immobilized type XIV collagen. J Biol Chem. 1995;270:16724-30 pubmed
    ..The association of procollagen I N-proteinase with a FACIT (fibril-associated collagens with interrupted triple helices) collagen as found here might be of physiological significance. ..
  6. Tortorella M, Burn T, Pratta M, Abbaszade I, Hollis J, Liu R, et al. Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science. 1999;284:1664-6 pubmed
    ..The identification of this protease provides a specific target for the development of therapeutics to prevent cartilage degradation in arthritis. ..
  7. Kashiwagi M, Enghild J, Gendron C, Hughes C, Caterson B, Itoh Y, et al. Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. J Biol Chem. 2004;279:10109-19 pubmed
    ..Finding of ADAMTS-4 in the interleukin-1alpha-treated porcine articular cartilage primarily as a 46-kDa form suggests that it exhibits a broader substrate spectrum in the tissue than originally considered. ..
  8. Pratta M, Scherle P, Yang G, Liu R, Newton R. Induction of aggrecanase 1 (ADAM-TS4) by interleukin-1 occurs through activation of constitutively produced protein. Arthritis Rheum. 2003;48:119-33 pubmed
    ..Thus, the activator could be a potential target by which to control aggrecanase-mediated degradation in arthritic diseases. ..
  9. Cross N, Chandrasekharan S, Jokonya N, Fowles A, Hamdy F, Buttle D, et al. The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican. Prostate. 2005;63:269-75 pubmed
    ..The negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer. ..
  10. Song R, Tortorella M, Malfait A, Alston J, Yang Z, Arner E, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 2007;56:575-85 pubmed
    ..Despite the apparent dominant role of ADAMTS-5 in genetically modified mice, our data suggest that both ADAMTS-4 and ADAMTS-5 contribute to the structural damage that characterizes human OA. ..
  11. Gao G, Westling J, Thompson V, Howell T, Gottschall P, Sandy J. Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. J Biol Chem. 2002;277:11034-41 pubmed
    ..We suggest that in vivo production of proteolytically active ADAMTS4 requires not only removal of the prodomain by a furin-like activity but also MMP-mediated removal of a portion of the C-terminal spacer domain. ..
  12. Hashimoto G, Aoki T, Nakamura H, Tanzawa K, Okada Y. Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett. 2001;494:192-5 pubmed
    ..These results suggest that TIMP-3 is a potent inhibitor against the aggrecanase activity of ADAMTS4 in vivo. ..
  13. Chockalingam P, Zeng W, Morris E, Flannery C. Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS-4 (aggrecanase 1) or ADAMTS-5 (aggrecanase 2). Arthritis Rheum. 2004;50:2839-48 pubmed
  14. Wang W, Ge G, Lim N, Nagase H, Greenspan D. TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. Biochem J. 2006;398:515-9 pubmed
    ..In contrast, TIMP-3 is demonstrated to inhibit ADAMTS-2 in vitro with apparent Ki values of 160 and 602 nM, in the presence of heparin or without respectively; and TIMP-3 is shown to inhibit procollagen processing by cells. ..
  15. Tortorella M, Pratta M, Liu R, Abbaszade I, Ross H, Burn T, et al. The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. J Biol Chem. 2000;275:25791-7 pubmed
    ..3) Aggrecanase-1 was not effective in cleaving glycosaminoglycan-free aggrecan. Taken together, these data suggest that the TSP-1 motif of aggrecanase-1 is critical for substrate recognition and cleavage. ..
  16. Satoh K, Suzuki N, Yokota H. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) is transcriptionally induced in beta-amyloid treated rat astrocytes. Neurosci Lett. 2000;289:177-80 pubmed
    ..Our results suggest a degradation of the extracellular matrix occurring in the brain of AD patients and a possibly significant role of this enzyme in the progression of AD. ..
  17. Sandy J, Westling J, Kenagy R, Iruela Arispe M, Verscharen C, Rodriguez Mazaneque J, et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem. 2001;276:13372-8 pubmed
    ..We conclude that versican V1 proteolysis in vivo can be catalyzed by one or more members of the ADAMTS family of metalloproteinases. ..
  18. Colige A, Vandenberghe I, Thiry M, Lambert C, Van Beeumen J, Li S, et al. Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3. J Biol Chem. 2002;277:5756-66 pubmed
    ..The potential function of ADAMTS-14 as a physiological aminoprocollagen peptidase in vivo is discussed. ..
  19. Nagase H, Kashiwagi M. Aggrecanases and cartilage matrix degradation. Arthritis Res Ther. 2003;5:94-103 pubmed
  20. Fernandes R, Hirohata S, Engle J, Colige A, Cohn D, Eyre D, et al. Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis. J Biol Chem. 2001;276:31502-9 pubmed
    ..The findings provide an explanation for the sparing of cartilage in dermatosparaxis and, perhaps, for the relative sparing of some procollagen I-containing tissues. ..
  21. Flannery C, Little C, Hughes C, Curtis C, Caterson B, Jones S. IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage. Matrix Biol. 2000;19:549-53 pubmed
    ..This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2. ..
  22. Tortorella M, Pratta M, Liu R, Austin J, Ross O, Abbaszade I, et al. Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4). J Biol Chem. 2000;275:18566-73 pubmed
    ..These data elucidate the sites and efficiency of cleavage during aggrecan degradation by aggrecanase and suggest potential tools for monitoring aggrecan cleavage in arthritis. ..
  23. Gendron C, Kashiwagi M, Lim N, Enghild J, Thøgersen I, Hughes C, et al. Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. J Biol Chem. 2007;282:18294-306 pubmed
    ..Our studies suggest that ADAMTS-5 is a major aggrecanase in cartilage metabolism and pathology. ..
  24. Naito S, Shiomi T, Okada A, Kimura T, Chijiiwa M, Fujita Y, et al. Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int. 2007;57:703-11 pubmed
  25. Tortorella M, Liu R, Burn T, Newton R, Arner E. Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biol. 2002;21:499-511 pubmed
    ..Finally, the zymogen of stromelysin (MMP-3) was not activated by either ADAM-TS4 or ADAM-TS5. ..
  26. Stanton H, Rogerson F, East C, Golub S, Lawlor K, Meeker C, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434:648-52 pubmed
  27. Mosyak L, Georgiadis K, Shane T, Svenson K, Hebert T, McDonagh T, et al. Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008;17:16-21 pubmed
    ..On this basis, we propose that mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active. ..
  28. Tortorella M, Malfait A, Deccico C, Arner E. The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation. Osteoarthritis Cartilage. 2001;9:539-52 pubmed
    ..5) Immunodepletion of both ADAM-TS4 and ADAM-TS5 from bovine articular cartilage cultures following IL-1 stimulation resulted in a 90% reduction of aggrecanase activity in the culture medium. ..
  29. Glasson S, Askew R, Sheppard B, Carito B, Blanchet T, Ma H, et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 2004;50:2547-58 pubmed
    ..The elucidation of the relative importance of ADAMTS-4 in the pathologic process of human OA will require examination of human OA tissues and evidence of disease modification in patients following therapeutic intervention. ..
  30. Troeberg L, Fushimi K, Scilabra S, Nakamura H, Dive V, Thøgersen I, et al. The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3. Matrix Biol. 2009;28:463-9 pubmed publisher
    ..5-fold better K(i) value for full-length ADAMTS-5 than for the catalytic and disintegrin domain alone. We propose that the C-terminal domains of the enzymes affect the structure around the active site, favouring interaction with TIMP-3. ..
  31. Minobe K, Ono R, Matsumine A, Shibata Minoshima F, Izawa K, Oki T, et al. Expression of ADAMTS4 in Ewing's sarcoma. Int J Oncol. 2010;37:569-81 pubmed
    ..We also demonstrated that ADAMTS4 protein was highly expressed in tumor samples of the patients with EWS by using immunohistochemistry. These results suggest that ADAMTS4 is a novel tumor marker for EWS. ..
  32. Osborn B, Bai Y, Plaas A, Sandy J. Image analysis of aggrecan degradation in articular cartilage with formalin-fixed samples. Methods Mol Med. 2007;135:167-82 pubmed
  33. Lauer Fields J, Spicer T, Chase P, Cudic M, Burstein G, Nagase H, et al. Screening of potential a disintegrin and metalloproteinase with thrombospondin motifs-4 inhibitors using a collagen model fluorescence resonance energy transfer substrate. Anal Biochem. 2008;373:43-51 pubmed
    ..Selective inhibitors for ADAMTS-4 would allow a more definitive evaluation of this protease in osteoarthritis and also represent a potential next generation in metalloproteinase therapeutics. ..
  34. Yu D, Tiilikainen P, Raustia A, Pirttiniemi P. Dietary loading and aggrecanase-1/TIMP-3 expression in rat mandibular condylar cartilage. J Orofac Pain. 2007;21:232-8 pubmed
    ..The temporary change in aggrecanase-1 and TIMP-3 expression reflects the complex interaction of these enzymes in the physiologic range and cartilage response to altered dietary loading. ..
  35. Hopper D, Vera M, How D, Sabatini J, Xiang J, Ipek M, et al. Synthesis and biological evaluation of ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides: a class of potent aggrecanase-1 inhibitors. Bioorg Med Chem Lett. 2009;19:2487-91 pubmed publisher
    ..The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity. ..
  36. Nakada M, Miyamori H, Kita D, Takahashi T, Yamashita J, Sato H, et al. Human glioblastomas overexpress ADAMTS-5 that degrades brevican. Acta Neuropathol. 2005;110:239-46 pubmed
    ..These results demonstrate for the first time that ADAMTS-5 is capable of degrading brevican and is overexpressed in glioblastoma cells, and suggest that ADAMTS-5 may play a role in glioma cell invasion through the cleavage of brevican. ..
  37. Nakamura M, Sone S, Takahashi I, Mizoguchi I, Echigo S, Sasano Y. Expression of versican and ADAMTS1, 4, and 5 during bone development in the rat mandible and hind limb. J Histochem Cytochem. 2005;53:1553-62 pubmed
  38. Mayer G, Hamelin J, Asselin M, Pasquato A, Marcinkiewicz E, Tang M, et al. The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates. J Biol Chem. 2008;283:2373-84 pubmed
    ..A similar mechanism may also apply to the convertase PACE4, thereby extending our knowledge of the molecular details of the zymogen activation and functions of these heparan sulfate proteoglycan-bound convertases. ..
  39. Lin Z, Fitzgerald J, Xu J, Willers C, Wood D, Grodzinsky A, et al. Gene expression profiles of human chondrocytes during passaged monolayer cultivation. J Orthop Res. 2008;26:1230-7 pubmed publisher
    ..This data may prove important for the future development of more specific and efficacious cultivation techniques for human articular chondrocyte-based therapies. ..
  40. Connelly J, Wilson C, Levenston M. Characterization of proteoglycan production and processing by chondrocytes and BMSCs in tissue engineered constructs. Osteoarthritis Cartilage. 2008;16:1092-100 pubmed publisher
    ..PG turnover does not appear to play a major role in the development of tissue engineered cartilage constructs by BMSCs. ..
  41. Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, et al. Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem. 2000;275:38885-90 pubmed
  42. Roughley P, Barnett J, Zuo F, Mort J. Variations in aggrecan structure modulate its susceptibility to aggrecanases. Biochem J. 2003;375:183-9 pubmed
    ..Thus, for aggrecan cleavage by aggrecanases, variations in cleavage efficiency exist with respect to the species and age of the animal from which the aggrecan is derived and the type of aggrecanase being used. ..
  43. Takizawa M, Yatabe T, Okada A, Chijiiwa M, Mochizuki S, Ghosh P, et al. Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS Lett. 2008;582:2945-9 pubmed publisher
    ..These data suggest that CaPPS could function as chondroprotective agent for the treatment of osteoarthritis by inhibition of ADAMTS4 through interaction with the C-terminal ancillary domain. ..
  44. Bogen O, Joseph E, Chen X, Levine J. GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci. 2008;28:12-9 pubmed publisher
    ..Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype. ..
  45. Thomas M, Sabatini M, Bensaude F, Mignard B, Ortuno J, Caron I, et al. A microplate assay for the screening of ADAMTS-4 inhibitors. Matrix Biol. 2006;25:261-7 pubmed
    ..This assay allows the rapid screening of aggrecanase inhibitors in a 96-well plate format, allowing an immediate transposition to high-throughput scale up. ..
  46. Glasson S. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets. 2007;8:367-76 pubmed
    ..These results indicate that the evaluation of genetically modified mice will become increasingly important as we unravel the genes contributing to OA. ..
  47. Ruggiero F, Roulet M, Bonod Bidaud C. [Dermis collagens: beyond their structural properties]. J Soc Biol. 2005;199:301-11 pubmed
    ..There is no doubt that the ongoing and future work using in vivo approaches will provide new cues regarding the function of collagens in dermis. ..
  48. Fosang A, Little C. Drug insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Clin Pract Rheumatol. 2008;4:420-7 pubmed publisher
    ..ADAMTS-4 and ADAMTS-5 are appropriate targets for OA therapies, but ultimately, inhibitors of these enzymes will form only part of a larger arsenal of therapies. ..
  49. Fushimi K, Troeberg L, Nakamura H, Lim N, Nagase H. Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. J Biol Chem. 2008;283:6706-16 pubmed
    ..However, removal of the spacer domain from ADAMTS-4 greatly enhanced more general proteolytic activity against non-aggrecan substrates, e.g. E. coli-expressed interglobular domain, fibromodulin, and carboxymethylated transferrin. ..
  50. Westra J, Limburg P, de Boer P, van Rijswijk M. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann Rheum Dis. 2004;63:1453-9 pubmed
    ..01 microM RWJ 67657. RWJ 67657 inhibits major proinflammatory mediator production in stimulated RSF at pharmacologically relevant concentrations. These findings could have important relevance for the treatment of rheumatoid arthritis. ..
  51. Bogen O, Dina O, Gear R, Levine J. Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican. Neuroscience. 2009;159:780-6 pubmed publisher
  52. Schnabel L, Lynch M, van der Meulen M, Yeager A, Kornatowski M, Nixon A. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J Orthop Res. 2009;27:1392-8 pubmed publisher
    ..Both MSC and AdIGF-MSC injection resulted in significantly improved tendon histological scores. These findings indicate a benefit to the use of MSCs and AdIGF-MSCs for the treatment of tendinitis. ..
  53. Wang K, Vishwanath P, Eichler G, Al Sebaei M, Edgar C, Einhorn T, et al. Analysis of fracture healing by large-scale transcriptional profile identified temporal relationships between metalloproteinase and ADAMTS mRNA expression. Matrix Biol. 2006;25:271-81 pubmed