Hippo Signaling Pathway In Pathogenesis And Progression Of ONFH

Osteonecrosis,commonly present in the femoral head,is the necrosis of trabecular bones caused by loss of blood supply,which leads to progressive joint destruction and motion limitation.Long-term or high-dose glucocorticoid therapy is the leading etiology of osteonecrosis.Glucocorticoid-induced inhibition of hypoxia-inducible factor 1?(HIF1?)plays an important role in the pathogenesis and progression of osteonecrosis.However,mechanistically how glucocorticoids inhibit HIF1? remains unclear.Here,we identified Yesassociated protein(YAP),the effector of the Hippo pathway,as a downstream mediator of glucocorticoid-induced signaling transduction in HIF-1? inhibition.Activation of YAP promotes HIF-1? degradation by enhancing the expression of GNB2L1,also known as receptor for activated C kinase 1(RACK1),in BMSCs.We further demonstrated that glucocorticoid promotes YAP activation through a cross-talk between glucocorticoid receptor(GR)and LATS kinase.Cytoplasmic GR blocks the binding of PP1 A to LATS kinase and thus increases the activity of LATS kinase which inactivates YAP.When glucocorticoids exist,cytoplasmic GR translocates to nucleus and further leads to YAP activation.Based on our finding,we rescued glucocorticoid-induced HIF-1? suppression by targeting YAP with statins and successfully prevented osteonecrosis in rats exposed to high-dose glucocorticoids.The p H of bone tissues in osteonecrosis decreased significantly due to its avascular and hypoxic nature.We found that decreased extracellular p H resulted in YAP activation which further impaired angiogenesis and tissue repair.We demonstrated that proton-sensing G-protein-coupled receptors(GPCRs)are required for the p H-dependent YAP activation.In addition,we report that decreased extracellular p H promotes the transformation of mesenchymal stem cells(MSCs)into cancer-associated fibroblasts(CAFs)by YAP activation.CAF activation dwarfed the differentiation potential of BMSC and further inhibited bone regeneration and repair.Based on our findings,we concluded that YAP is a key molecule in osteonecrosis pathogenesis and progression.