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Increasing evidence has indicated that excessive adipogenesis contributes to osteoporosis.Therefore,trans-differentiation of adipogenic committed preadipocytes into osteoblasts may be a potential therapeutical approach for osteoporosis.We explored whether bone morphogenic protein 9 (BMP9) could induce 3T3-L1 preadipocytes to trans-differentiate into osteoblasts.BMP9 effectively increased expression of osteogenic markers and promoted mineralization in preadipocytes.However,BMP9 also induced adipogenic differentiation of preadipocytes,as evidenced by increased lipid accumulation and up-regulation of adipogenesis-related transcription factors.In order to regulate the switch between osetogenesis and adipogenesis,we evaluated the effect of all-trans retinoic acid (ATRA) on BMP9-induced differentiation of preadipocytes.We showed that ATRA enhanced BMP9-induced osteogenic differentiation and blocked BMP9-induced adipogenic differentiation both in vitro and in vivo.Mechanistically,ATRA was shown to up-regulate BMP9 expression and activate BMP/Smad signaling.Additionally,BMP9 and ATRA exerted a synergistic effect on activation of Wnt/β-catenin signaling.Knockdown of β-catenin abolished the stimulatory effect of ATRA on BMP9-induced alkaline phosphatase activity and reversed the inhibitory effect of ATRA on BMP9-induced adipogenesis in preadipocytes.Furthermore,ATRA and BMP9 synergistically repressed glycogen synthase kinase 3β(GSK3β) activity and promoted Akt phosphorylation,and inhibited expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) that antagonizes phosphatidylinositol-3-kinase (PI3K) function,suggesting that Wnt/p- catenin signaling was activated at least partly through PI3K/Akt/GSK3p pathway.Collectively,ATRA mediated BMP9-induced osteogenic or adipogenic differentiation of 3T3-LI preadipocytes by BMP/Smad and Wnt/p-catenin signaling.The combination of BMP9 and ATRA may be explored as an effective therapeutic strategy for osteoporosis.