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Treatment of the bone pathologies, particularly osteoclast\u2010mediated subchondral bone loss in the early stages of OA, could prevent subsequent cartilage degeneration and progression of OA. In the present study, the PKC inhibitor, Sotrastaurin, was found to inhibit RANKL\u2010induced osteoclast formation in vitro in a dose\u2010 and time\u2010dependent manner. In particular, SO exerted its anti\u2010osteoclastic effect predominantly at the early stages of RANKL stimulation, suggesting inhibitory effects on precursor cell fusion. Using mature osteoclasts cultured on bovine bone discs, we showed that SO also exerts anti\u2010resorptive effects on mature osteoclasts bone resorptive function. Mechanistically, SO attenuates the early activation of the p38, ERK and JNK signalling pathways, leeding to impaired induction of crucial osteoclast transcription factors c\u2010Jun, c\u2010Fos and NFATc1. We also showed that SO treatment significantly inhibited the phosphorylation of PKC\u03b4 and MARCKS, an upstream regulator of cathepsin K secretion. Finally, in animal studies, SO significantly alleviates the osteochondral pathologies of subchondral bone destruction as well as articular cartilage degeneration following DMM\u2010induced OA, markedly improving OARSI scores. The reduced subchondral bone loss was associated with marked reductions in TRAP(+) osteoclasts in the subchondral bone tissue. Collectively, our data provide evidence for the protective effects of SO against OA by preventing aberrant subchondral bone and articular cartilage changes. Thus, SO demonstrates potential for further development as an alternative therapeutic option against OA.<\/jats:p>","DOI":"10.1111\/jcmm.15404","type":"journal-article","created":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T17:38:24Z","timestamp":1594489104000},"page":"8452-8465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Sotrastaurin, a PKC inhibitor, attenuates RANKL\u2010induced bone resorption and attenuates osteochondral pathologies associated with the development of OA"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7263-3785","authenticated-orcid":false,"given":"Cong","family":"Pang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Ninth Affiliated Hospital of Guangxi Medical University Beihai China"},{"name":"Department of Orthopedics Shaoxing People's Hospital (Shaoxing Hospital Zhejiang University School of Medicine) Shaoxing 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