title: Disturbed MEK/ERK signaling increases osteoclast activity via the Hedgehog-Gli pathway in postmenopausal osteoporosis.
abstract: Postmenopausal osteoporosis is a worldwide health problem and is characterized by increased and activated osteoclasts. However, the mechanism by which osteoclasts are dysregulated in postmenopausal osteoporosis is not fully understood. In this study, we found that the Hedgehog-Gli pathway was upregulated in postmenopausal osteoporotic osteoclasts and that 17β-estradiol both inhibited osteoclastogenesis and induced osteoclast apoptosis by downregulating Hedgehog-Gli signaling. Furthermore, we demonstrated that the Hedgehog-Gli pathway was negatively regulated by MEK/ERK signaling and that this effect was Sonic Hedgehog (SHH)-dependent and was partially blocked by an anti-SHH antibody. Moreover, we found that the stimulatory effect of Hedgehog signaling on osteoclastogenesis and the inhibitory effect on osteoclast apoptosis were dependent on the Gli family of transcription factors. The pathways and molecules that contribute to the regulation of osteoclastogenesis and apoptosis represent potential new strategies for designing molecular drugs for the treatment of postmenopausal osteoporosis.
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China; Team of Aviation Physical Examination for Flying Cadet Recruiting, Air Force General Hospital, Beijing, People's Republic of China; Department of Orthopaedics, Air Force General Hospital, Beijing, People's Republic of China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jie
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Engineering Research Center of Orthopedic Implants, First Affiliated Hospital of the CPLA General Hospital, Beijing, People's Republic of China.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, First Affiliated Hospital, Chengdu Medical College, Chengdu, People's Republic of China.
authors.forename: Yangjing
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics, Air Force General Hospital, Beijing, People's Republic of China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Du
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. Electronic address: yangliu@fmmu.edu.cn.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. Electronic address: zjluofmmu@hotmail.com.
authors.forename: Zhuojing
authors.initials: Z
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D015663:Osteoporosis, Postmenopausal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000067996:RAW 264.7 Cells; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: D004967:Estrogens; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Canonical hedgehog signaling; Estrogen; MEK/ERK; Osteoclast; Postmenopausal osteoporosis; SHH