OSMRβ-mediated signals on resident fibroblasts restore healing in diabetic skin wounds through promoting angiogenesis and granulation tissue formation

Oncostatin M (OSM) has various biological activities through OSM receptor β (OSMRβ) in many conditions such as inflammation and tissue regeneration, but it remains elusive on its precise roles in skin wound healing. Especially, diabetic mice showed impaired wound healing with suppressed expression of OSM and OSMRβ. Here we show the pathophysiological roles of OSM-OSMRβ axis in skin wound healing utilizing wild-type (WT) and Osmrb−/− mice. Excisional wounds induced OSM expression in infiltrating neutrophils and macrophages and OSMRβ expression in fibroblasts. Compared with WT mice, Osmrb−/− mice exhibited delayed wound healing despite a similar extent of leukocyte infiltration. The analysis on bone marrow chimeric mice revealed that OSMRβ-expressing resident cells contributed to wound healing process. The absence of OSMRβ suppressed the expression of TIMP-1 and HGF in fibroblasts, which are associated with reduction in collagen deposition and neovascularization, respectively. Moreover, OSM induced TIMP-1 and HGF expression in a murine fibroblast cell line with MAP activation. Actually, topical OSM application in diabetic wounds enhanced the expression of HGF and TIMP-1 at the wound sites, eventually resulting in accelerated wound healing. Thus, the OSM-OSMRβ axis and/or its downstream signaling pathways may be a novel therapeutic target to treat diabetic skin wounds. OSM–OSMRβ promotes fibroblast TIMP-1/HGF expression, collagen deposition, and angiogenesis, accelerating wound healing; its loss delays repair, while topical OSM improves diabetic wounds, suggesting a therapeutic target.