Bone morphogenetic protein 9 (BMP9) has remarkable potential to induce the differentiation of mesenchymal stem cells (MSCs) towards the osteoblastic lineage. Additionally,research suggests that certain growth factors have the ability to potentiate BMP9-inducedosteogenic differentiation of MSCs. Sonic Hedgehog (Shh) plays an indispensable role in theregulation of skeletal development. The objective of this research was to assess the potentialinfluence of Shh on BMP9-induced osteogenic differentiation of MSCs. Our findings indicatedthat Shh effectively enhanced BMP9-induced early and late osteogenic differentiation of MSCs,and increased BMP9-induced expression/transcriptional activity of osteogenesis-related transcription factors. Besides, it was observed that Shh promoted BMP9-induced ectopic bone formation of MSCs in vivo. Moreover, BMP9 was able to facilitate the repair of bone defects inrats, while Shh further accelerated this reparative process. Mechanistically, Shh enhancedthe activation of the Smad1/5/8 signaling pathway which was induced by BMP9. Furthermore,GANT-61, an inhibitor of Gli1 and Gli2, attenuated the enhancing effect of Shh on BMP9-induced osteogenic differentiation of MSCs. Collectively, the co-administration of BMP9 andShh may present a promising therapeutic approach for the treatment of fracture nonunion, delayed fracture healing, and bone defects.
Lulu ZhangCaixia JiZiyun LiHabu JiwaZhou XieXiaoji LuoJinyong Luo
Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.
un WenHao TangMingfen TianLing WangQinghuan YangYong ZhaoXuemei LiYu RenJiani WangLi ZhouYongjun TanHaiyun WuXinrui CaiYilin WangHui CaoJianfeng XuQin Yang
