The role of TIMPs in regulation of extracellular matrix proteolysis

Matrix Biol. May-Jul 2015;44-46:247-54. doi: 10.1016/j.matbio.2015.03.005. Epub 2015 Mar 21.

Abstract

Tissue inhibitors of metalloproteinases (TIMPs), which inhibit matrix metalloproteinases (MMPs) as well as the closely related, a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs), were traditionally thought to control extracellular matrix (ECM) proteolysis through direct inhibition of MMP-dependent ECM proteolysis. This classical role for TIMPs suggests that increased TIMP levels results in ECM accumulation (or fibrosis), whereas loss of TIMPs leads to enhanced matrix proteolysis. Mice lacking TIMP family members have provided support for such a role; however, studies with these TIMP deficient mice have also demonstrated that loss of TIMPs can often be associated with an accumulation of ECM. Collectively, these studies suggest that the divergent roles of TIMPs in matrix accumulation and proteolysis, which together can be referred to as ECM turnover, are dependent on the TIMP, specific tissue, and local tissue environment (i.e. health vs. injury/disease). Ultimately, these combined factors dictate the specific metalloproteinases being regulated by a given TIMP, and it is likely the diversity of metalloproteinases and their physiological substrates that determines whether TIMPs inhibit matrix proteolysis or accumulation. In this review, we discuss the evidence for the dichotomous roles of TIMPs in ECM turnover highlighting some of the common findings between different TIMP family members. Importantly, while we now have a better understanding of the role of TIMPs in regulating ECM turnover, much remains to be determined. Data on the specific metalloproteinases inhibited by different TIMPs in vivo remains limited and must be the focus of future studies.

Keywords: Fibrosis; Matrix turnover; Metalloproteinases; TIMPs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Extracellular Matrix / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Matrix Metalloproteinases / metabolism
  • Proteolysis
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism*

Substances

  • Tissue Inhibitor of Metalloproteinases
  • Matrix Metalloproteinases