MMP13
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMMP13, CLG3, MANDP1, MMP-13, Matrix metallopeptidase 13, MDST
External IDsOMIM: 600108 MGI: 1340026 HomoloGene: 20548 GeneCards: MMP13
Orthologs
SpeciesHumanMouse
Entrez

4322

17386

Ensembl

ENSG00000137745

ENSMUSG00000050578

UniProt

P45452

P33435

RefSeq (mRNA)

NM_002427

NM_008607

RefSeq (protein)

NP_002418

NP_032633

Location (UCSC)Chr 11: 102.94 – 102.96 MbChr 9: 7.27 – 7.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene.[5][6] It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form.[7] MMP-13 has a predicted molecular weight around 54 kDa.[8] It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain PDB: 1PEX​. 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.[9]

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.[6]

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.[10]

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. [11]

Clinical Relevance

MMP-13 has long been a protein of interest in the context of osteoarthritis and rheumatoid arthritis.[12]

The role of MMP-13 has also been thoroughly examined in atherosclerosis, specifically in potentially reducing the collagen content of the fibrous cap. [13] [14] [15] [16] [17]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137745 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050578 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Freije JM, Díez-Itza I, Balbín M, Sánchez LM, Blasco R, Tolivia J, López-Otín C (June 1994). "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. doi:10.1016/S0021-9258(19)89457-7. hdl:20.500.12792/5105. PMID 8207000.
  6. 1 2 "Entrez Gene: MMP13 matrix metallopeptidase 13 (collagenase 3)".
  7. ↑ Cui N, Hu M, Khalil RA (2017). "Biochemical and Biological Attributes of Matrix Metalloproteinases". Progress in Molecular Biology and Translational Science. 147: 1–73. doi:10.1016/bs.pmbts.2017.02.005. ISBN 9780128116371. PMC 5430303. PMID 28413025.
  8. ↑ "MMP13 (human)". www.phosphosite.org. Retrieved 2021-10-05.
  9. ↑ Johansson N, Ahonen M, Kähäri VM (January 2000). "Matrix metalloproteinases in tumor invasion". Cellular and Molecular Life Sciences. 57 (1): 5–15. doi:10.1007/s000180050495. PMID 10949577. S2CID 1551605.
  10. ↑ Leeman MF, Curran S, Murray GI (2003). "The structure, regulation, and function of human matrix metalloproteinase-13". Critical Reviews in Biochemistry and Molecular Biology. 37 (3): 149–66. doi:10.1080/10409230290771483. PMID 12139441. S2CID 40814227.
  11. ↑ Yu H, Fellows A, Foote K, Yang Z, Figg N, Littlewood T, Bennett M (March 2018). "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. doi:10.1161/ATVBAHA.117.310502. PMC 5828387. PMID 29326312.
  12. ↑ Takaishi H, Kimura T, Dalal S, Okada Y, D'Armiento J (February 2008). "Joint diseases and matrix metalloproteinases: a role for MMP-13". Current Pharmaceutical Biotechnology. 9 (1): 47–54. doi:10.2174/138920108783497659. PMID 18289056.
  13. ↑ Sukhova GK, Schönbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P (May 1999). "Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques". Circulation. 99 (19): 2503–9. doi:10.1161/01.cir.99.19.2503. PMID 10330380.
  14. ↑ Deguchi JO, Aikawa E, Libby P, Vachon JR, Inada M, Krane SM, Whittaker P, Aikawa M (October 2005). "MMP-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques". Circulation. 112 (17): 2708–2715. doi:10.1161/CIRCULATIONAHA.105.562041. PMID 16230484. S2CID 5981752.
  15. ↑ Cheng C, Tempel D, van Haperen R, van Damme L, Algür M, Krams R, de Crom R (May 2009). "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. doi:10.1016/j.atherosclerosis.2009.01.025. PMID 19233360.
  16. ↑ Quillard T, Tesmenitsky Y, Croce K, Travers R, Shvartz E, Koskinas KC, et al. (November 2011). "Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (11): 2464–72. doi:10.1161/ATVBAHA.111.231563. PMC 3200308. PMID 21903941.
  17. ↑ Quillard T, Araújo HA, Franck G, Tesmenitsky Y, Libby P (June 2014). "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. doi:10.1161/ATVBAHA.114.303326. PMC 4123424. PMID 24723558.

Further reading

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