β-Lapachone Regulates the Transforming Growth Factor-β–Smad Signaling Pathway Associated with Collagen Biosynthesis in Human Dermal Fibroblasts

Abstract

The transforming growth factor (TGF)-β-Smad signaling pathway regulates collagen biosynthesis in human dermal fibroblasts. We found that β-lapachone stimulated type I collagen expression in human dermal fibroblasts. In this study, we evaluated whether the β-lapachone-induced upregulation of collagen biosynthesis in human dermal fibroblasts is associated with the TGF-β-Smad signaling pathway. In cultured human dermal fibroblasts, both Smad 2 and Smad 3 (Smad 2/3) were phosphorylated by β-lapachone treatment in a concentration-dependent manner. SB431542, a specific inhibitor of TGF-β receptor I kinase, inhibited the β-lapachone-mediated Smad 2/3 phosphorylation and type I collagen expression, suggesting that β-lapachone stimulates collagen production via the TGF-β receptor I kinase-dependent pathway. β-Lapachone did not increase TGF-β1 synthesis in human dermal fibroblasts, suggesting that the molecular mechanism of β-lapachone for the upregulation of collagen synthesis is due to the extracellular regulation of availability and activities of TGF-β. This study provides new insights into the role of β-lapachone in collagen synthesis in human dermal fibroblasts and suggests that β-lapachone can be used as a pharmacological tool to study collagen homeostasis associated with TGF-β-Smad signaling. Key words β-lapachone; collagen; human dermal fibroblast; Smad; transforming growth factor-βSkin regeneration treatments are of considerable interest to cosmeceutical researchers and dermatologists for treating skin damage that is primarily induced by aging and exposure to sunlight. Various noninvasive treatments and topical cosmeceuticals are used to treat symptoms of photo-aged skin, including wrinkles.1-3) Aging can be induced by intrinsic and extrinsic factors that reduce collagen synthesis and increase the levels of matrix metalloproteinases, which results in degradation of the connective tissue network. 4-6)Type I collagen is the most abundant structural protein in skin connective tissue and it confers strength and resilience to skin. Type I collagen is primarily synthesized by fibroblasts residing within the skin connective tissue. Type I procollagen, a soluble precursor of collagen, is secreted by fibroblasts and then proteolytically processed to form insoluble collagen fibers. Disorganization, fragmentation, and dispersion of collagen bundles are prominent features of photodamaged human skin. 7,8)Transforming growth factor (TGF)-β regulates extracellular matrix (ECM) metabolism and genesis of tissue fibrosis through overproduction of type I collagen.9-12) Several signaling pathways, including the Smad and ERK pathways, mediate TGF-β-induced extracellular matrix production and fibrosis.13-15) Members of the TGF-β family regulate numerous cellular activities, including cell differentiation and ECM production, 16,17) and are the primary stimulators for ECM production. In addition, other cytokines, such as connective tissue growth factor and interleukin-4, may also contribute to elevated collagen deposition.18) In fibrobl...

Effects of dietary proline on swim bladder collagen synthesis and its possible regulation by the TGF‐β/Smad pathway in spotted drum, Nibea diacanthus

“…For instance, Smad binding element CAGACA located at −263 to −258 bp of the collagen type I alpha 2 (COL1A2) promoter is thought to be one of the most potent mediators of COL1A2 promoter activity in ventricular fibrosis and collagen synthesis (Masatoshi, 2010). Recently, transforming growth factor (TGF)‐β/Smad signalling pathway has emerged as a potential mediator of cell growth and differentiation, playing a critical role in the regulation of collagen synthesis (Park, Jeong, & Kim, 2016; Tang et al., 2011; Zhao, Shi, Dang, Zhai, & Ye, 2015). It has been reported that the autocrine TGF‐β signalling hypothesis can explain the intrinsic activation of collagen promoter in systemic sclerosis fibroblasts (Masatoshi, 2010).…”