title: TNF-α promotes osteoclastogenesis through JNK signaling-dependent induction of Semaphorin3D expression in estrogen-deficiency induced osteoporosis.
abstract: Tumor necrosis factor α (TNF-α)-induced osteoclast formation have been demonstrated to play an important role in the pathogenesis of estrogen deficiency-mediated bone loss, but the exact mechanisms by which TNF-α enhanced osteoclast differentiation were not fully elucidated. The class III semaphorins members were critical to regulate bone homeostasis. Here, we identified a novel mechanism whereby TNF-α increasing Semaphorin3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin3D expression was upregulated by TNF-α during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-α on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-α-induced Semaphorin3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin3D expression by TNF-α. In addition, silencing of Semaphorin3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin3D and suggested that increased Semaphorin3D may contribute to enhanced bone loss by increased TNF-α in estrogen deficiency-induced osteoporosis. Thus, Semaphorin3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis.
authors.affiliation: Department of Orthopaedics, Second Military Medical University's Jinan Clinical Medicine College, Jinan, China.|Department of Orthaopedics, General Hospital of Jinan Military Command, Jinan, Shandong, P. R. China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Sang
authors.affiliation: Taian City Central Hospital, Department of Traumatology, Taian City, Shandong, P. R. China.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Second Military Medical University's Jinan Clinical Medicine College, Jinan, China.|Department of Orthaopedics, General Hospital of Jinan Military Command, Jinan, Shandong, P. R. China.
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Second Military Medical University's Jinan Clinical Medicine College, Jinan, China.|Department of Orthaopedics, General Hospital of Jinan Military Command, Jinan, Shandong, P. R. China.
authors.forename: Fangjing
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Second Military Medical University's Jinan Clinical Medicine College, Jinan, China.|Department of Orthaopedics, General Hospital of Jinan Military Command, Jinan, Shandong, P. R. China.
authors.forename: Xuecheng
authors.initials: X
authors.lastname: Cao
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China.
authors.forename: Lei
authors.identifier: http://orcid.org/0000-0001-5143-3234
authors.initials: L
authors.lastname: Guo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D010024:Osteoporosis / Q000378:metabolism*; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D004967:Estrogens; D053245:RANK Ligand; D039961:Semaphorins; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4
keywords: JNK signaling; Osteoclastogenesis; Semaphorin3D; TNF-α; proliferation