The Endogenous Protease Inhibitor TIMP-1 Mediates Protection and Recovery from Cutaneous Photodamage

Abstract

UVB exposure is well known to induce skin photodamage and photoaging that correlates with qualitative and quantitative deterioration of the dermal extracellular matrix (ECM) because of the upregulation of matrix metalloproteinases (MMPs). Although inhibitory effects of tissue inhibitor of metalloproteinases (TIMPs) on most MMPs have been reported, the protective role of TIMP-1 against photodamage is poorly understood. To address this, TIMP-1 function was augmented or abolished in a human skin xenograft photodamage model after the confirmation of significantly diminished TIMP-1 expression both in photoaged and intrinsically aged skins. During a chronic UVB exposure regimen, pre-treatment with a lentiviral vector overexpressing TIMP-1 or concomitant administration of an anti-TIMP-1-neutralizing antibody (NAB) led to photoprotection or more severe photodamage, respectively. Overexpression of TIMP-1 resulted in significant inhibition of UVB-induced ECM degradation, as well as suppression of decreased skin elasticity and roughness, whereas the NAB-mediated inhibition of TIMP-1 had opposite effects. Furthermore, UVB-induced production of the pro-inflammatory cytokine, tumor necrosis factor α, was inhibited by TIMP-1 treatment of human keratinocytes. Taken together, these data shed light on the important role of TIMP-1 in protection and recovery from cutaneous photodamage because of its suppression of ECM degradation and inflammation.

Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice

“…3). We cannot completely exclude the possibility that changes in COL1 deposition in bat mutants reflects a non-specific reduction of ECM molecules as a consequence of FRAS1-FREM-complex disruption; however, the reduced COL1 deposition observed is consistent with the associations between COL1 and both PDGFC and TIMP1 reported in the literature (Lai et al, 2011; Yokose et al, 2012). Thus, we propose that FREM1 mutation alters its association with PDGFC and thereby alters the cascade of downstream PDGFRα signalling events, changing the expression profile of proteases and inhibitors (such as TIMP1) to aberrantly impact ECM deposition.…”

“…Collagen I (COL1) is a fibrillar collagen that is present in the dermis and basement membrane, and its skin deposition was most recently shown to be specifically regulated by TIMP1 activity (Yokose et al, 2012). In the absence of a reliable antibody to directly detect murine TIMP1, as a proxy for TIMP1 activity in vivo we examined basement membrane COL1 deposition in fetal head skin in mice at E13.5, with an antibody to native COL1 (Fig.…”

“…Interestingly, TIMP1 activity regulates COL1 deposition in the skin (Yokose et al, 2012) and transgenic mice overexpressing PDGFC in the liver develop fibrosis with increased COL1 content (Lai et al, 2011), whereas PDGFC and PDGFRα knockout mice develop skin blistering (Soriano, 1997; Tallquist and Soriano, 2003). Here we demonstrate that FREM1 bat mutants also exhibit reduced TIMP1 expression and lowered basement membrane COL1 deposition (Fig.…”

Effect of Adipose-Derived Stem Cells on Induced Photoaging in the Skin of Adult Guinea Pig: Histological and Immunohistochemical Study

“…Guinea pigs of all four subgroups were sacrificed under anesthesia using 30 mg/kg pentobarbital [6] . Scarification was done after three weeks from the beginning of the experiment (the shaving day).…”

“…Individuals of all skin types can manifest photoaging, and unfortunately, photocarcinogenesis could be the most serious complication of chronic UV radiation exposure [6] .…”