Abstract
Glycoprotein nonmetastatic melanoma protein B (GPNMB) is involved in various cell functions such as cell adhesion, migration, proliferation, and differentiation. In this study, we set forth to determine the role of GPNMB in systemic sclerosis (SSc) fibroblasts. Dermal fibroblasts were isolated from skin biopsies from healthy subjects and patients with diffuse cutaneous (dc)SSc. GPNMB was upregulated in dcSSc fibroblasts compared to normal fibroblasts, and correlated negatively with the modified Rodnan skin score. In addition, dcSSc fibroblasts secreted higher levels of soluble (s)GPNMB (147.4 ± 50.2 pg/ml vs. 84.8 ± 14.8 pg/ml, p<0.05), partly due to increased ADAM10. sGPNMB downregulated profibrotic genes in dcSSc fibroblasts and inhibited cell proliferation and gel contraction. The anti-fibrotic effect of sGPNMB was at least in part mediated through CD44, which is regulated by histone acetylation. TGFβ downregulated GPNMB and decreased the release of its soluble form in normal fibroblasts. In dcSSc fibroblasts, GPNMB is upregulated by its own soluble form. Our data demonstrate an anti-fibrotic role of sGPNMB in SSc and established a role for the ADAM10-sGPNMB-CD44 axis in dermal fibroblasts. Upregulating GPNMB expression might provide a novel therapeutic approach in SSc.
Highlights
Systemic sclerosis is an autoimmune disease that affects the immune and vascular systems, and causes fibrosis in multiple organs
We found that diffuse cutaneous SSc (dcSSc) fibroblasts produced significantly higher amounts of sGPNMB than normal fibroblasts (Figure 1F)
We found that knockdown of CD44 in these cells led to significant downregulation of COL1A1 while it had no effect on ACTA2 (Figure 2F). sGPNMB did not downregulate COL1A1 and ACTA2 in CD44 knocked down cells compared to cells sGPNMB downregulated COL1A1 and ACTA2 at the mRNA level in dcSSc fibroblasts. (C) sGPNMB significantly reduced cell proliferation of dcSSc fibroblasts at a dose-dependent manner
Summary
Systemic sclerosis (scleroderma, SSc) is an autoimmune disease that affects the immune and vascular systems, and causes fibrosis in multiple organs. Progressive organ fibrosis, in the lungs, is the leading cause of death in SSc. GPNMB in Scleroderma Fibrosis [1]. Glycoprotein nonmetastatic melanoma protein B (GPNMB), known as osteoactivin or dendritic cell-associated heparan sulfate proteoglycan-integrin ligand (DC-HIL), is a highly glycosylated protein that is localized on cell membranes or stored in endosomes and lysosomes [2]. It is widely expressed in many cell types and has a wide array of functions that are critical for various physiological and pathological processes. Soluble (s)GPNMB has been shown to mediate its effect through engaging with CD44, a transmembrane glycoprotein involved in cell-matrix or cell-cell interactions [2]
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