The role of TIMPs in regulation of extracellular matrix proteolysis

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.

Mechanisms of Lung Fibrosis Resolution

“…28 These studies and others now demonstrate that the MMPs and TIMPs influence several cellular processes, including proliferation, survival, and inflammation, that directly or indirectly influence myofibroblast activation and ECM turnover. 23,24,29,30 Cross-linking of collagen and elastin are posttranslational modifications of the ECM that can hinder fibrosis resolution by preventing extracellular proteolytic enzymes from accessing binding sites. One family of enzymes mediating this cross-linking is lysyl oxidase and its homologues (lysyl oxidaseelike enzymes 1 to 4).…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…Endorepellin is found in vivo, where it is proteolytically processed from perlecan (14) via matrix metalloproteinases, a family of enzymes involved in a multitude of biological processes (35)(36)(37)(38)(39). Although perlecan mRNA can undergo alternative splicing, no evidence exists for endorepellin production in vivo via this mechanism (14).…”

COPD affected lung tissue remodelling due to the local distribution of MMP-2, TIMP-2, TGF-β1 and HSP-70

“…To maintain the stability of ECM environment, TIMP-2 directly inhibits MMP-2; therefore, the location of TIMP-2 is crucial. Aft er the release, both active form and pro-active form of MMPs are regulated by the activity of TIMPs [1]. In COPD, imbalance of proteases (MMPs) and antiproteases (TIMPs) induces structural changes in the form of pathological tissue repair and airway remodelling [17].…”

“…Increased levels of TIMPs promote ECM accumu lation towards fi brosis, whereas the decrease of TIMPs enhances proteolysis in ECM. TIMPs regulate MMPs within ECM by inhibiting their maintenance [1,6,7]. Overall eff ective ECM remodelling in lung tissue is regulated as a dynamic balance between the proper cell and tissue renewal and, conversely, the tissue degradation.…”