title: The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone.
abstract: Fibrous dysplasia (FD) is characterized by the replacement of normal bone with abnormal fibro-osseous tissue. This disorder is due to activating missense mutations in the GNAS gene and resultant over-production of cAMP. However, the signalling pathways that contribute to FD pathogenesis remain unknown. In the current study, bone marrow stromal cells (BMSCs) carrying GNAS R201H mutation were isolated from lesion site of FD patients. cAMP accumulation, enhanced proliferation and impaired osteogenesis potential were observed. Two cell models, BMSCs treated with excess exogenous cAMP and BMSCs infected with lentivirus GNAS R201H, were established to model the pathological conditions of FD and used to investigate its pathogenesis. The results suggest that the CREB-Smad6-Runx2 axis is involved in osteogenesis dysfunction of BMSCs with the FD phenotype. We confirmed the results in FD lesion-derived BMSCs and observed that the impaired osteogenesis potential of BMSCs infected with lentivirus GNAS (R201H) was recovered in vitro through modulation of the CREB-Smad6-Runx2 axis. This study provides useful insight into the signalling pathways involved in the FD phenotype and facilitates dissection of the molecular pathogenesis of FD and testing of novel therapies.
authors.affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Qi-Ming
authors.initials: QM
authors.lastname: Fan
authors.forename: Bing
authors.initials: B
authors.lastname: Yue
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Bian
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Tu
authors.forename: Ke-Rong
authors.initials: KR
authors.lastname: Dai
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Tang
mesh_terms: D000293:Adolescent; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002864:Chromogranins; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010012:Osteogenesis / Q000187:drug effects; D011994:Recombinant Proteins; D015398:Signal Transduction; D051905:Smad6 Protein / Q000378:metabolism*; D014161:Transduction, Genetic; D055815:Young Adult
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D002864:Chromogranins; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D011994:Recombinant Proteins; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D002118:Calcium