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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. [ABSTRACT FROM AUTHOR]

CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein-coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13-/- and B1R-/- mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases. [ABSTRACT FROM AUTHOR]