title: α-Melanocyte stimulating hormone attenuates dexamethasone-induced osteoblast damages through activating melanocortin receptor 4-SphK1 signaling.
abstract: Long-term glucocorticoid (GC) usage may cause non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) is shown to exert potent cytotoxic effect to osteoblasts. Here, we investigated the potential activity of α-melanocyte stimulating hormone (α-MSH) against the process. Our data revealed that pretreatment of α-MSH significantly inhibited Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. Melanocortin receptor 4 (MC4R) acts as the receptor of α-MSH in mediating its actions in osteoblasts. The MC4R antagonist SHU9119, or shRNA-mediated knockdown of MC4R, almost abolished α-MSH-induced activation of downstream signalings (Akt and Erk1/2) and its pro-survival effect in osteoblasts. Further studies showed that α-MSH activated MC4R downstream sphingosine kinase 1 (SphK1) and increased cellular sphingosine-1-phosphate (S1P) content in MC3T3-E1 cells and primary murine osteoblasts, which were blocked by SHU9119 or MC4R shRNAs. SphK1 inhibition by the its inhibitor N,N-dimethylsphingosine (DMS), or SphK1 knockdown by targeted-shRNAs, largely attenuated α-MSH-mediated osteoblast protection against Dex. Together, these results suggest that α-MSH alleviates Dex-induced damages to cultured osteoblasts through activating MC4R-SphK1 signaling.
authors.affiliation: Department of Intensive Care Unit, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, PR China.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xie
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, PR China.
authors.forename: Jian-bo
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, PR China. Electronic address: huaiaifengjidr@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Ji
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, PR China.
authors.forename: Shouguo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, PR China.
authors.forename: Haodong
authors.initials: H
authors.lastname: Fei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000521:alpha-MSH / Q000008:administration & dosage*; D000099157:Sphingosine Kinase
chemical_list: D003907:Dexamethasone; D017853:Phosphotransferases (Alcohol Group Acceptor); D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; D000099157:Sphingosine Kinase
keywords: Dexamethasone; Melanocortin receptor 4 (MC4R) and sphingosine kinase 1 (SphK1); Osteoblasts; α-Melanocyte stimulating hormone (α-MSH)