Abstract
ObjectivePeriostin, a novel matricellular protein, is recently reported to play a crucial role in tissue remodeling and is highly expressed under fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma.MethodsUsing skin from patients and healthy donors, the expression of periostin was assessed by immunohistochemistry and immunoblotting analyses. Furthermore, we investigated periostin−/− (PN−/−) and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate-buffered saline. Bleomycin-induced fibrotic changes were compared in PN−/− and WT mice by histological analysis as well as by measurements of profibrotic cytokine and extracellular matrix protein expression levels in vivo and in vitro. To determine the downstream pathway involved in periostin signaling, receptor neutralizing antibody and signal transduction inhibitors were used in vitro.ResultsElevated expression of periostin was observed in the lesional skin of patients with scleroderma compared with healthy donors. Although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased numbers of myofibroblasts after bleomycin treatment, PN−/− mice showed resistance to these changes. In vitro, dermal fibroblasts from PN−/− mice showed reduced transcript expression of alpha smooth actin and procollagen type-I alpha 1 (Col1α1) induced by transforming growth factor beta 1 (TGFβ1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by blocking the αv integrin-mediated PI3K/Akt signaling either with anti-αv functional blocking antibody or with the PI3K/Akt kinase inhibitor LY294002.ConclusionPeriostin plays an essential role in the pathogenesis of Bleomycin-induced scleroderma in mice. Periostin may represent a potential therapeutic target for human scleroderma.
Highlights
Scleroderma is a connective tissue disorder with unknown etiology
To investigate the involvement of matricellular proteins in the pathogenesis of scleroderma, we focused on a novel matricellular protein, periostin, a 90-kDa, secreted, homophilic cell adhesion protein
To assess the involvement of periostin in the pathogenesis of scleroderma, we first compared the expression of periostin in sclerotic skin lesions from scleroderma patients and skin from identical areas of healthy donors
Summary
Scleroderma is a connective tissue disorder with unknown etiology. The disease is characterized by excessive deposition of collagen and other extracellular matrix (ECM) proteins, resulting in fibrosis of skin and other visceral organs [1]. Despite much effort, there is still no established treatment for fibrosis in scleroderma. The ECM of the skin is composed of structural proteins such as collagen type-I but of many different proteins that modulate cellular behavior. The interactions among various ECM proteins provide molecular signals to resident cells including dermal fibroblasts and play essential roles in the maintenance and turnover of the ECM. ECM proteins are considered as key players in the pathogenesis of scleroderma
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