title: The inhibition effects of insulin on BMP2-induced muscle heterotopic ossification.
abstract: Bone morphogenetic proteins (BMPs) play an important role in regulating osteoblastic differentiation and bone formation. But the diffuse of BMPs into muscle tissues around bone injury sites often leads to heterotopic ossification, which has been regarded as one of major side-effects of BMP implementation in bone defect patients. It raises great demands for exploring effective methods that preventing BMP-induced heterotopic ossification while not interrupting the osteoinductive activity of BMPs for in situ bone defect repair. Here we found insulin, a positive regulator for bone regeneration, inhibited BMP2-induced muscle heterotopic ossification by suppressing the expression of bone transcription factor Osterix. By analyzing downstream molecules of insulin pathway, we found AKT/mTOR/GSK3 signaling was responsible for the inhibition of insulin on BMP2-induced ossification, and GSK3 inhibitor SB216763 attenuated BMP2-induced muscle heterotopic ossification. The data might shed light on developing effective clinical therapy for inhibiting muscle heterotopic ossification when BMPs were used bone defect repair.
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Cardiac Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Jianzhou
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiac Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Miao
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Road, 400038, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: jwdai@genetics.ac.cn.
authors.forename: Jianwu
authors.initials: J
authors.lastname: Dai
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry*; D001861:Bone Regeneration / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology*; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D007328:Insulin; C493716:Runx2 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
keywords: AKT; BMP2; Heterotopic ossification; Insulin; Osterix