Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 34, Issue 5, Pages 911-922Publisher
WILEY
DOI: 10.1002/jbmr.3655
Keywords
OSTEOPOROSIS; OSTEOCLAST; ADAM12; P38
Categories
Funding
- Medical and Health Science and Technology Planning Project of Zhejiang Province [2017KY082, 2018KY493]
- Natural Science Foundation of Zhejiang Province [LY18H060001, LQ18H250001, LY16H060004]
- Key Project of Zhejiang Provincial Natural Science Foundation [LZ15H06002]
- Key Project of Zhejiang Medical Science and Technology Plan [2016145597]
- National Natural Science Foundation of China [81871797, 81601925]
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Pamapimod (PAM) is a novel selective p38 mitogen-activated protein (MAP) kinase inhibitor proved to be effective in rheumatoid arthritis in phase 2 clinical trial. However, its effect on osteoclast-associated osteoporosis and the underlying mechanisms remain unclear. In this study, we showed that PAM suppressed receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation via inhibition of p38 phosphorylation and subsequent c-Fos and nuclear factor of activated T cells c1 (NFATc1) expression. In addition, the downregulated NFATc1 leads to reduced expression of its targeting gene disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), which was further proven to be critical for osteoclastic bone resorption. Therefore, we treated ovariectomized (OVX) mice with PAM and revealed a protective effect of PAM on osteoporosis in vivo. In conclusion, our results demonstrated PAM can prevent OVX-induced bone loss through suppression of p38/NFATc1-induced osteoclast formation and NFATc1/ADAM12-associated bone resorption. (c) 2018 American Society for Bone and Mineral Research.
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