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Biochem J. Apr 1, 1998; 331(Pt 1): 341–346.
PMCID: PMC1219357

Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1).


Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-alpha, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.

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Selected References

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  • Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197–250. [PubMed]
  • Vincenti MP, Clark IM, Brinckerhoff CE. Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? Arthritis Rheum. 1994 Aug;37(8):1115–1126. [PubMed]
  • Vincenti MP, White LA, Schroen DJ, Benbow U, Brinckerhoff CE. Regulating expression of the gene for matrix metalloproteinase-1 (collagenase): mechanisms that control enzyme activity, transcription, and mRNA stability. Crit Rev Eukaryot Gene Expr. 1996;6(4):391–411. [PubMed]
  • Hasty KA, Pourmotabbed TF, Goldberg GI, Thompson JP, Spinella DG, Stevens RM, Mainardi CL. Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J Biol Chem. 1990 Jul 15;265(20):11421–11424. [PubMed]
  • Freije JM, Díez-Itza I, Balbín M, Sánchez LM, Blasco R, Tolivia J, López-Otín C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994 Jun 17;269(24):16766–16773. [PubMed]
  • Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF, Hambor JE. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest. 1996 Feb 1;97(3):761–768. [PMC free article] [PubMed]
  • Borden P, Solymar D, Sucharczuk A, Lindman B, Cannon P, Heller RA. Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes. J Biol Chem. 1996 Sep 20;271(38):23577–23581. [PubMed]
  • Brenner DA, O'Hara M, Angel P, Chojkier M, Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. [PubMed]
  • Conca W, Kaplan PB, Krane SM. Increases in levels of procollagenase mRNA in human fibroblasts induced by interleukin-1, tumor necrosis factor-alpha, or serum follow c-jun expression and are dependent on new protein synthesis. Trans Assoc Am Physicians. 1989;102:195–203. [PubMed]
  • Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. J Clin Invest. 1996 May 1;97(9):2011–2019. [PMC free article] [PubMed]
  • Wernicke D, Seyfert C, Hinzmann B, Gromnica-Ihle E. Cloning of collagenase 3 from the synovial membrane and its expression in rheumatoid arthritis and osteoarthritis. J Rheumatol. 1996 Apr;23(4):590–595. [PubMed]
  • Lindy O, Konttinen YT, Sorsa T, Ding Y, Santavirta S, Ceponis A, López-Otín C. Matrix metalloproteinase 13 (collagenase 3) in human rheumatoid synovium. Arthritis Rheum. 1997 Aug;40(8):1391–1399. [PubMed]
  • Henriet P, Rousseau GG, Eeckhout Y. Cloning and sequencing of mouse collagenase cDNA. Divergence of mouse and rat collagenases from the other mammalian collagenases. FEBS Lett. 1992 Sep 28;310(2):175–178. [PubMed]
  • Schorpp M, Mattei MG, Herr I, Gack S, Schaper J, Angel P. Structural organization and chromosomal localization of the mouse collagenase type I gene. Biochem J. 1995 May 15;308(Pt 1):211–217. [PMC free article] [PubMed]
  • Borella L, Eng CP, DiJoseph J, Wells C, Ward J, Caccese R, Baeder WL. Rapid induction of early osteoarthritic-like lesions in the rabbit knee by continuous intra-articular infusion of mammalian collagenase or interleukin-1. Agents Actions. 1991 Sep;34(1-2):220–222. [PubMed]
  • Arner EC, Harris RR, DiMeo TM, Collins RC, Galbraith W. Interleukin-1 receptor antagonist inhibits proteoglycan breakdown in antigen induced but not polycation induced arthritis in the rabbit. J Rheumatol. 1995 Jul;22(7):1338–1346. [PubMed]
  • Hembry RM, Bagga MR, Murphy G, Henderson B, Reynolds JJ. Rabbit models of arthritis: immunolocalization of matrix metalloproteinases and tissue inhibitor of metalloproteinase in synovium and cartilage. Am J Pathol. 1993 Aug;143(2):628–642. [PMC free article] [PubMed]
  • Fini ME, Plucinska IM, Mayer AS, Gross RH, Brinckerhoff CE. A gene for rabbit synovial cell collagenase: member of a family of metalloproteinases that degrade the connective tissue matrix. Biochemistry. 1987 Sep 22;26(19):6156–6165. [PubMed]
  • Auble DT, Brinckerhoff CE. The AP-1 sequence is necessary but not sufficient for phorbol induction of collagenase in fibroblasts. Biochemistry. 1991 May 7;30(18):4629–4635. [PubMed]
  • Chamberlain SH, Hemmer RM, Brinckerhoff CE. Novel phorbol ester response region in the collagenase promoter binds Fos and Jun. J Cell Biochem. 1993 Jul;52(3):337–351. [PubMed]
  • Fini ME, Austin SD, Holt PT, Ruby PL, Gross RH, White HD, Brinckerhoff CE. Homology between exon-containing portions of rabbit genomic clones for synovial cell collagenase and human foreskin and synovial cell mRNAs. Coll Relat Res. 1986 Jul;6(3):239–248. [PubMed]
  • Vincenti MP, Coon CI, Lee O, Brinckerhoff CE. Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms. Nucleic Acids Res. 1994 Nov 11;22(22):4818–4827. [PMC free article] [PubMed]
  • Vincenti MP, Coon CI, White LA, Barchowsky A, Brinckerhoff CE. src-related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP-1, in interleukin-1-stimulated synovial fibroblasts. Arthritis Rheum. 1996 Apr;39(4):574–582. [PubMed]
  • Chandrasekhar S, Harvey AK. Differential regulation of metalloprotease steady-state mRNA levels by IL-1 and FGF in rabbit articular chondrocytes. FEBS Lett. 1992 Jan 20;296(2):195–200. [PubMed]
  • Caccese RG, DiJoseph JF, Skotnicki JS, Borella LE, Adams LM. Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989. Agents Actions. 1991 Sep;34(1-2):223–225. [PubMed]
  • Lefebvre V, Peeters-Joris C, Vaes G. Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes. Biochim Biophys Acta. 1990 May 22;1052(3):366–378. [PubMed]
  • Lin CW, Georgescu HI, Phillips SL, Evans CH. Cycloheximide inhibits the induction of collagenase mRNA in chondrocytes exposed to synovial factors or recombinant interleukin-1. Agents Actions. 1989 Jun;27(3-4):445–447. [PubMed]
  • Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996 Jan 25;379(6563):335–339. [PubMed]
  • Girard MT, Matsubara M, Kublin C, Tessier MJ, Cintron C, Fini ME. Stromal fibroblasts synthesize collagenase and stromelysin during long-term tissue remodeling. J Cell Sci. 1993 Apr;104(Pt 4):1001–1011. [PubMed]
  • Gross RH, Sheldon LA, Fletcher CF, Brinckerhoff CE. Isolation of a collagenase cDNA clone and measurement of changing collagenase mRNA levels during induction in rabbit synovial fibroblasts. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1981–1985. [PMC free article] [PubMed]
  • Brinckerhoff CE, Suzuki K, Mitchell TI, Oram F, Coon CI, Palmiter RD, Nagase H. Rabbit procollagenase synthesized and secreted by a high-yield mammalian expression vector requires stromelysin (matrix metalloproteinase-3) for maximal activation. J Biol Chem. 1990 Dec 25;265(36):22262–22269. [PubMed]

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