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Prog Biophys Mol Biol. 2016 Nov;122(2):101-111. doi: 10.1016/j.pbiomolbio.2016.05.008. Epub 2016 May 11.

Disturbed MEK/ERK signaling increases osteoclast activity via the Hedgehog-Gli pathway in postmenopausal osteoporosis.

Author information

1
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.
2
Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
3
Beijing Engineering Research Center of Orthopedic Implants, First Affiliated Hospital of the CPLA General Hospital, Beijing, People's Republic of China.
4
Department of Orthopaedics, First Affiliated Hospital, Chengdu Medical College, Chengdu, People's Republic of China.
5
Department of Orthopaedics, Air Force General Hospital, Beijing, People's Republic of China.
6
Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. Electronic address: yangliu@fmmu.edu.cn.
7
Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. Electronic address: zjluofmmu@hotmail.com.

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.

KEYWORDS:

Canonical hedgehog signaling; Estrogen; MEK/ERK; Osteoclast; Postmenopausal osteoporosis; SHH

[Indexed for MEDLINE]

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