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The Role of Timps in Regulation of Extracellular Matrix Proteolysis

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The Role of Timps in Regulation of Extracellular Matrix Proteolysis Review The role of TIMPs in regulation of extracellular matrix proteolysis Valerie Arpino a,d, Michael Brock a,d and Sean E. Gill a,b,c,d a - Centre for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada b - Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada c - Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada d - Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada Correspondence to Sean E. Gill: 800 Commissioners Road East, Centre for Critical Illness Research, Victoria Research Labs, A6-134, London, ON, N6A 5W9, Canada. [email protected] http://dx.doi.org/10.1016/j.matbio.2015.03.005 Edited by W.C. Parks and S. Apte 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. © 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction the current paper and can be found in a number of excellent reviews [4–7]. There are four homo- The tissue inhibitors of metalloproteinases logous members of the TIMP family [1–3]. General- (TIMPs) are tissue specific, endogenous inhibitors ly, all TIMPs are capable of inhibiting all known of metalloproteinases, including the matrix metallo- MMPs; however, the efficacy of MMP inhibition proteinases (MMPs) as well as the closely related, varies with each TIMP. For example, TIMP1 is a a disintegrin and metalloproteinases (ADAMs) strong inhibitor of many MMPs except for some and ADAMs with thrombospondin motifs (ADAMTSs) of the membrane type (MT)-MMPs, including [1–3]. In the current paper, various MMPs and ADAMs MMP14, -15, -16, -19, and -24 [1,2]. As well, both will be mentioned as it pertains to the role of the TIMP1 and -3 associate with latent or pro-MMP9 different TIMPs; however, complete descriptions of while TIMP2, -3 and -4 are capable of interaction these metalloproteinases is beyond the scope of with pro-MMP2 [1]. 0022-2836/© 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Matrix Biol. (2015) 44–46, 247–254 248 The role of TIMPs in regulation of extracellular matrix proteolysis TIMPs also inhibit ADAMs and ADAMTSs, deposition, and all of these process have been although, this inhibition is primarily accomplished found to be controlled by TIMPs (Fig. 1). by TIMP3. The proteolytic activity of ADAM10 can be Collectively, these findings suggest that TIMPs inhibited by TIMP1 and -3, whereas TIMP3 alone is can both directly inhibit ECM proteolysis as well as an efficient inhibitor of ADAMTS4 and -TS5, which indirectly control ECM turnover and that the are postulated to cleave aggrecan, a component specific roles for each TIMP is likely dependent of cartilage matrix [8–10]. TIMP3 can also inhibit on the metalloproteinases inhibited by the given ADAM12S mediated cleavage of insulin-like growth TIMP within a specific, local tissue environment factor binding protein (IGFBP) 3 and -5 [11], and (i.e. health vs. injury/disease; Table 1; Fig. 1). The TIMP3, or the N-terminal domain of TIMP3, subsequent sections will describe the evidence for specifically inhibits ADAM17 [12,13]. each of the TIMPs in direct inhibition of ECM Localization of TIMPs is important in the control proteolysis as well as indirect regulation of ECM of TIMP function. TIMP1, -2, and -4 were initially turnover. thought to be soluble inhibitors, whereas TIMP3 was localized to the extracellular matrix (ECM) TIMP1 through interaction with heparan sulfate and other sulfated proteoglycans [14]. More recently TIMPs have been shown to localize with cell surface Direct Inhibition of ECM proteolysis by TIMP1 proteins; however, this interaction has primarily been associated with metalloproteinase-indepen- Many pathological conditions, including the forma- dent functions for the various TIMPs and as yet, tion of scar tissue, pulmonary fibrosis and diabetic has not been found to impact ECM turnover [15– nephropathy, are associated with excessive deposi- 19]. For instance, TIMP1 has been shown to tion of ECM components leading to fibrosis [22–24]. mediate angiogenesis through interaction with β1 Interestingly, TIMP1 expression is increased within integrin and CD63 [16,17]. Additionally, TIMP3 has these profibrotic environments, which suggests a been shown to antagonize vascular endothelial role for TIMP1 in restricting ECM proteolysis. For growth factor (VEGF) signaling by binding directly example, TIMP1 expression is increased in mesan- to the VEGF receptor [18,19]. gial cells treated with recombinant human connec- Initial evidence for the role of TIMPs in ECM tive tissue growth factor in conjunction with high proteolysis was the ability of TIMPs to inhibit various glucose concentrations, which replicates the condi- MMPs in vitro and the association of increased tions causing diabetic nephropathy [24]. This in- expression of TIMPs with an accumulation of matrix crease in TIMP1 is associated with a significant (i.e. lung fibrosis) [20]. Ultimately, this belief led to reduction in the matrix degradative capacity of the generally accepted idea that the balance mesangial cells, and the addition of a TIMP1 between MMPs and TIMPs was responsible for neutralizing antibody abolishes this reduction in the ECM proteolysis, and that a shift in the balance matrix degradative capacity [24]. in favor of MMPs resulted in increased ECM Mice lacking TIMP1 (Timp1−/− mice) have provid- proteolysis, whereas a shift in the balance in favor ed additional evidence supporting the role of TIMP1 of TIMPs resulted in protection of the ECM and in control of ECM proteolysis within the cardiovas- decreased proteolysis. Importantly, examination of cular system. Timp1−/− mice exhibit increased left the phenotypes of mice lacking different TIMPs ventricular wall stress due to decreased myocardial demonstrated that TIMPs have many different roles, fibrillar collagen content as discovered by compar- one of which is directly regulating ECM proteolysis ative endocardiographic studies, suggesting TIMP1 (Fig. 1). plays a role in the preservation of normal myocardial It has become apparent, however, that the structure and function [25]. Furthermore, when fed balance between metalloproteinases and TIMPs an atherogenic Western-type diet, Timp1−/− mice controls much more than simply ECM proteolysis. In crossed with apolipoprotein E knockout (apoEO) fact, studies using mice genetically deficient for mice exhibited a greater number of abdominal aortic different metalloproteinases or TIMPs have demon- aneurysms, characterized by infiltrated macro- strated that metalloproteinases process many bio- phages and extensively fragmented elastic lamellae, logically active proteins, including cytokines, compared to that of apoEO mice alone [26]. Such chemokines, and cell surface proteins [7,21].Fur- gelatinolytic activity present at the site of the aortic thermore, regulation of these biologically active rupture was eliminated with the addition of recombi- proteins by the metalloproteinase/TIMP axis has nant TIMP1 [26]. Collectively, both the expression an indirect effect on matrix turnover in many studies as well as the functional studies in Timp1−/− instances. For example, altered transforming mice strongly suggest that TIMP1 has the ability to growth factor (TGF) β signaling, inflammation, or attenuate degradation of the extracellular matrix in the number of myofibroblast-like cells all potentially healthy tissues as well as under pathological alter ECM turnover leading to increased ECM conditions. The role of TIMPs in regulation of extracellular matrix proteolysis 249 Fig. 1. The diverse functions
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