Recent advances in understanding the regulation of metalloproteinases.

Young, David A ORCID: 0000-0002-7078-6745, Barter, Matt J and Wilkinson, David J ORCID: 0000-0002-6262-3575 (2019) Recent advances in understanding the regulation of metalloproteinases. F1000Research, 8. F1000 Faculty Rev-195-.

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Abstract

Metalloproteinases remain important players in arthritic disease, in part because members of this large enzymatic family, namely matrix metalloproteinase-1 (MMP-1) and MMP-13, are responsible for the irreversible degradation of articular cartilage collagen. Although direct inhibition of MMPs fell out of vogue with the initial clinical disappointment of the first generation of compounds, interest in other mechanisms that control these important enzymes has always been maintained. Since these enzymes are critically important for tissue homeostasis, their expression and activity are tightly regulated at many levels, not just by direct inhibition by their endogenous inhibitors the tissue inhibitors of metalloproteinases (TIMPs). Focussing on MMP-13, we discuss recent work that highlights new discoveries in the transcriptional regulation of this enzyme, from defined promoter functional analysis to how more global technologies can provide insight into the enzyme's regulation, especially by epigenetic mechanisms, including non-coding RNAs. In terms of protein regulation, we highlight recent findings into enzymatic cascades involved in MMP-13 regulation and activation. Importantly, we highlight a series of recent studies that describe how MMP-13 activity, and in fact that of other metalloproteinases, is in part controlled by receptor-mediated endocytosis. Together, these new discoveries provide a plethora of novel regulatory mechanisms, besides direct inhibition, which with renewed vigour could provide further therapeutic opportunities for regulating the activity of this class of important enzymes.

Item Type:	Article
Uncontrolled Keywords:	Humans, Collagen, Tissue Inhibitor of Metalloproteinases, Endocytosis, Gene Expression Regulation, Matrix Metalloproteinase 13
Depositing User:	Symplectic Admin
Date Deposited:	30 Jan 2020 16:37
Last Modified:	13 Feb 2024 09:15
DOI:	10.12688/f1000research.17471.1
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3072720