Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure

Abstract

The loss of TGF␤ or its downstream mediator, Smad3, key players in tissue repair, accelerates closure of incisional wounds in mice. In contrast, we now report that excisional ear wounds in mice lacking Smad3 enlarge compared with wild-type controls resulting from changes in extracellular matrix molecules, which alter the mechanotransduction properties of these wounds. Specifically, levels of elastin and glycosoaminoglycans are increased, collagen fibers are more compactly organized, and matrix modulators like integrins, TGF␤1, and matrix metalloproteinases (MMPs) are altered both basally and after wounding in Smad3 knockout mice. Mechanical testing of dorsal skin correlates these changes in matrix composition with functional parameters, specifically an increased elastic modulus, suggesting an imbalance of tissue forces. We propose that the altered mechanical elastic properties translate into a persistent retractile force that is opposed by decreased wound contractile forces contributing to the enlarging ear wound in Smad3 knockout mice. These studies highlight a previously undescribed role for Smad3 in the mechanotransduction of matrix unsupported ear wound closure.TGF␤ ͉ tissue forces ͉ wound healing

α3β1 integrin–controlled Smad7 regulates reepithelialization during wound healing in mice

“…The changes in Smad2 and Smad3 activity in Itga3 -/-keratinocytes could partly explain the aberrant reepithelialization in Itga3 -/-skin since these Smads have been implicated in wound healing previously (8,33). For example, our results are consistent with observations of impaired wound healing in Smad3 heterozygous mice (8).…”

Erythropoietin improves skin wound healing and activates the TGF-β signaling pathway

“…[25][26][27][28][29] The complex role of Smads is further underlined by controversial data on the function of Smad3, as mice lacking Smad3 show accelerated wound healing, 30 but altered mechanotransduction due to changes in ECM molecules. 31 In the present study, EPO-induced acceleration of skin wound healing was associated with the upregulation of Smad2, -3, and -4 mRNA expression. In contrast to the agonistic Smads, Smad7 blocks TGF-b signal transduction, in part, by preventing the interaction of Smad2/-3 with the activated TGF-b type I receptor.…”

Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

“…TGF-b is primarily involved in many facets of epithelial and mesenchymal cellular behavior and insights into heterotypic TGF-b signaling by mesenchymal fibroblast modulating the malignant phenotype of the overlying epithelium has further complicated its role in vivo (Bhowmick et al, 2004;Egeblad et al, 2005;Radisky et al, 2007). A recent report using a small molecule kinase inhibitor of Alk5 (TGF-b RI) inhibiting the TGF-b pathway demonstrated efficacy in blocking the mesenchymal tumors while promoting the epithelial tumors in a transgenic mouse model (Laping et al, 2007) further emphasizing the multi-faceted nature of TGF-b in mediating biological outcomes based on cell lineages and tissue context as we have also observed in wound healing (Arany et al, 2006). Farnesyl transferase inhibition can result in differential downstream Ras and Non-Ras target gene expression, especially on Rho GTPases, that mediate TGF-b signaling and in turn could alter the cytoskeleton contributing to the transformed phenotype and anchorage-independent growth (Atfi et al, 1997;Lebowitz and Prendergast, 1998;Bhowmick et al, 2001;Prendergast, 2001) In this study, we use primary MEFs from S3WT and KO mice and Ras oncogene to analyse the role of the Smad3 in the TGF-b signaling pathway and in mediating malignant transformation.…”