title: All-trans retinoic acid modulates bone morphogenic protein 9-induced osteogenesis and adipogenesis of preadipocytes through BMP/Smad and Wnt/β-catenin signaling pathways.
abstract: It is known that excessive adipogenesis contributes to osteoporosis, suggesting that 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 led to adipogenic differentiation of preadipocytes, as evidenced by increased lipid accumulation and up-regulation of adipogenic 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 found that ATRA enhanced BMP9-induced osteogenic differentiation and blocked BMP9-induced adipogenic differentiation both in vitro and in vivo. Mechanistically, ATRA was shown to elevate 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/β-catenin signaling was activated at least partly through PI3K/Akt/GSK3β pathway. Collectively, ATRA mediated BMP9-induced osteogenic or adipogenic differentiation of 3T3-L1 preadipocytes by BMP/Smad and Wnt/β-catenin signaling. The combination of BMP9 and ATRA may be explored as an effective therapeutic strategy for osteoporosis.
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China.
authors.forename: Ranxi
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China.
authors.forename: Zhengjian
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Nie
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Yin
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing, China; Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
authors.forename: Baicheng
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: dengzhongliang7586@126.com.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Deng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000378:metabolism*; D055412:Growth Differentiation Factors / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010012:Osteogenesis / Q000187:drug effects*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; D014212:Tretinoin
keywords: Adipogenic differentiation; All-trans retinoic acid; Bone morphogenic protein 9; Osteogenic differentiation; Preadipocytes