Matrix metallopeptidase 13 explained

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene.^[1] It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form.^[2] MMP-13 has a predicted molecular weight around 54 kDa.^[3] It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain . Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.^[4]

Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMPs are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The protein encoded by this gene cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3.^[5]

Regulation

Transcriptional regulation of MMP-13 is tightly controlled due to its potent proteolytic capacity. There are several binding domains for various transcription factors including AP-1, PEA-3 and OSE-2 as well as a sequence with homology to a TGF-β inhibitory element (TIE). Moreover, several cytokines and growth factors have been demonstrated to affect Mmp13 gene expression, including parathyroid hormone, IGF-1, TGF-β, hepatocyte growth factor and many inflammatory cytokines such as IL-1α and IL-1β.^[6] The upstream regulatory region of the Mmp13 gene contains a number of transcription factor binding sites but it was recently discovered that there is a conserved forkhead response element (FHRE) consensus sequence for FOXO3a in the human, mouse and rat Mmp13 promoter. Endogenous FOXO3a activation results in marked upregulation of Mmp13 expression which is capable of promoting extracellular matrix degradation and apoptotic cell death. ^[7]

Clinical Relevance

MMP-13 has long been a protein of interest in the context of osteoarthritis and rheumatoid arthritis.^[8]

The role of MMP-13 has also been thoroughly examined in atherosclerosis, specifically in potentially reducing the collagen content of the fibrous cap.^{[9] [10] [11] [12] [13]}

Further reading

• Nagase H, Woessner JF . Matrix metalloproteinases . The Journal of Biological Chemistry . 274 . 31 . 21491–4 . July 1999 . 10419448 . 10.1074/jbc.274.31.21491 . free .
• Pendás AM, Matilla T, Estivill X, López-Otín C . The human collagenase-3 (CLG3) gene is located on chromosome 11q22.3 clustered to other members of the matrix metalloproteinase gene family . Genomics . 26 . 3 . 615–8 . April 1995 . 7607691 . 10.1016/0888-7543(95)80186-P .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF, Hambor JE . 6 . Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage . The Journal of Clinical Investigation . 97 . 3 . 761–8 . February 1996 . 8609233 . 507114 . 10.1172/JCI118475 .
• Knäuper V, Will H, López-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM, Murphy G . 6 . Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme . The Journal of Biological Chemistry . 271 . 29 . 17124–31 . July 1996 . 8663255 . 10.1074/jbc.271.29.17124 . free .
• Gomis-Rüth FX, Gohlke U, Betz M, Knäuper V, Murphy G, López-Otín C, Bode W . The helping hand of collagenase-3 (MMP-13): 2.7 A crystal structure of its C-terminal haemopexin-like domain . Journal of Molecular Biology . 264 . 3 . 556–66 . December 1996 . 8969305 . 10.1006/jmbi.1996.0661 .
• Knäuper V, Cowell S, Smith B, López-Otin C, O'Shea M, Morris H, Zardi L, Murphy G . 6 . The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction . The Journal of Biological Chemistry . 272 . 12 . 7608–16 . March 1997 . 9065415 . 10.1074/jbc.272.12.7608 . free .
• Pendás AM, Balbín M, Llano E, Jiménez MG, López-Otín C . Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13) . Genomics . 40 . 2 . 222–33 . March 1997 . 9119388 . 10.1006/geno.1996.4554 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Willmroth F, Peter HH, Conca W . A matrix metalloproteinase gene expressed in human T lymphocytes is identical with collagenase 3 from breast carcinomas . Immunobiology . 198 . 4 . 375–84 . February 1998 . 9562863 . 10.1016/s0171-2985(98)80046-6 .
• Lovejoy B, Welch AR, Carr S, Luong C, Broka C, Hendricks RT, Campbell JA, Walker KA, Martin R, Van Wart H, Browner MF . 6 . Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors . Nature Structural Biology . 6 . 3 . 217–21 . March 1999 . 10074939 . 10.1038/6657 . 36142262 .
• Barmina OY, Walling HW, Fiacco GJ, Freije JM, López-Otín C, Jeffrey JJ, Partridge NC . Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization . The Journal of Biological Chemistry . 274 . 42 . 30087–93 . October 1999 . 10514495 . 10.1074/jbc.274.42.30087 . free.
• Lauer-Fields JL, Tuzinski KA, Shimokawa K, Nagase H, Fields GB . Hydrolysis of triple-helical collagen peptide models by matrix metalloproteinases . The Journal of Biological Chemistry . 275 . 18 . 13282–90 . May 2000 . 10788434 . 10.1074/jbc.275.18.13282 . free .
• Hiller O, Lichte A, Oberpichler A, Kocourek A, Tschesche H . Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII . The Journal of Biological Chemistry . 275 . 42 . 33008–13 . October 2000 . 10930399 . 10.1074/jbc.M001836200 . free .
• McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I, Overall CM . Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 . Science . 289 . 5482 . 1202–6 . August 2000 . 10947989 . 10.1126/science.289.5482.1202 . 2000Sci...289.1202M .
• Terp GE, Christensen IT, Jørgensen FS . Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes . Journal of Biomolecular Structure & Dynamics . 17 . 6 . 933–46 . June 2000 . 10949161 . 10.1080/07391102.2000.10506582 . 1270176 .
• Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y . 6 . Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites . The Journal of Biological Chemistry . 275 . 49 . 38885–90 . December 2000 . 10986281 . 10.1074/jbc.M003875200 . free .

External links

• The MEROPS online database for peptidases and their inhibitors: M10.013

Notes and References

1. 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 . The Journal of Biological Chemistry . 269 . 24 . 16766–73 . June 1994 . 10.1016/S0021-9258(19)89457-7 . 8207000 . free . 20.500.12792/5105 . free .
2. Cui N, Hu M, Khalil RA . Biochemical and Biological Attributes of Matrix Metalloproteinases . Progress in Molecular Biology and Translational Science . 147 . 1–73 . 2017 . 28413025 . 5430303 . 10.1016/bs.pmbts.2017.02.005 . 9780128116371 .
3. Web site: MMP13 (human). 2021-10-05. www.phosphosite.org.
4. Johansson N, Ahonen M, Kähäri VM . Matrix metalloproteinases in tumor invasion . Cellular and Molecular Life Sciences . 57 . 1 . 5–15 . January 2000 . 10949577 . 10.1007/s000180050495 . 1551605 . 11147091 .
5. Web site: Entrez Gene: MMP13 matrix metallopeptidase 13 (collagenase 3).
6. Leeman MF, Curran S, Murray GI . The structure, regulation, and function of human matrix metalloproteinase-13 . Critical Reviews in Biochemistry and Molecular Biology . 37 . 3 . 149–66 . 2003 . 12139441 . 10.1080/10409230290771483 . 40814227 .
7. Yu H, Fellows A, Foote K, Yang Z, Figg N, Littlewood T, Bennett M . FOXO3a (Forkhead Transcription Factor O Subfamily Member 3a) Links Vascular Smooth Muscle Cell Apoptosis, Matrix Breakdown, Atherosclerosis, and Vascular Remodeling Through a Novel Pathway Involving MMP13 (Matrix Metalloproteinase 13) . Arteriosclerosis, Thrombosis, and Vascular Biology . 38 . 3 . 555–565 . March 2018 . 29326312 . 10.1161/ATVBAHA.117.310502 . 5828387 . free .
8. Takaishi H, Kimura T, Dalal S, Okada Y, D'Armiento J . Joint diseases and matrix metalloproteinases: a role for MMP-13 . Current Pharmaceutical Biotechnology . 9 . 1 . 47–54 . February 2008 . 18289056 . 10.2174/138920108783497659 .
9. Sukhova GK, Schönbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P . Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques . Circulation . 99 . 19 . 2503–9 . May 1999 . 10330380 . 10.1161/01.cir.99.19.2503 . free .
10. Deguchi JO, Aikawa E, Libby P, Vachon JR, Inada M, Krane SM, Whittaker P, Aikawa M . MMP-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. . Circulation . October 2005 . 112 . 17 . 2708–2715 . 10.1161/CIRCULATIONAHA.105.562041 . 16230484 . 5981752 . free .
11. Cheng C, Tempel D, van Haperen R, van Damme L, Algür M, Krams R, de Crom R . Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype . Atherosclerosis . 204 . 1 . 26–33 . May 2009 . 19233360 . 10.1016/j.atherosclerosis.2009.01.025 .
12. Quillard T, Tesmenitsky Y, Croce K, Travers R, Shvartz E, Koskinas KC, Sukhova GK, Aikawa E, Aikawa M, Libby P . 6 . Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis . Arteriosclerosis, Thrombosis, and Vascular Biology . 31 . 11 . 2464–72 . November 2011 . 21903941 . 10.1161/ATVBAHA.111.231563 . 3200308 . free .
13. Quillard T, Araújo HA, Franck G, Tesmenitsky Y, Libby P . Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata . Arteriosclerosis, Thrombosis, and Vascular Biology . 34 . 6 . 1179–86 . June 2014 . 24723558 . 10.1161/ATVBAHA.114.303326 . 4123424 . free .