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Front. Pharmacol. | doi: 10.3389/fphar.2018.00174

Flavopiridol protects bone tissue by attenuating RANKL induced osteoclast formation

Ziang Hu1, Yilei Chen1, Lijiang Song1, Jasper Yik2, Dominik Haudenschild2 and  Shunwu Fan1*
  • 1Orthopedic surgery department, Sir Run Run Shaw Hospital, China
  • 2Department of Orthopaedic Surgery, University of California, Davis, United States

Bone resorption and homeostasis is carried out by osteoclasts, whose differentiation and activity are regulated by the RANK/RANKL axis. Our previous studies using a mouse model of joint injury show that joint trauma induces local inflammation followed by bone remodeling. The transcription factor cyclin-dependent kinase 9 (CDK9) is the major regulator of inflammation, as CDK9 inhibitor flavopiridol effectively suppress injury-induced inflammatory response. The objective of this study was to investigate the underlying mechanism through which flavopiridol regulates bone resorption. The effects of CDK9 inhibition, by the specific-inhibitor flavopiridol, on bone resorption were determined in vivo using two distinct and clinically relevant bone remodeling models. The first model involved titanium particle-induced acute osteolysis, and the second model was ovariectomy-induced chronic osteoporosis. The effects and mechanism of CDK9 inhibition on osteoclastogenesis were examined using in vitro culture of bone marrow macrophages (BMM). Our results indicated that flavopiridol potently suppressed bone resorption in both in vivo bone-remodeling models. In addition, CDK9 inhibition suppressed in vitro osteoclastogenesis of BMM and reduced their expression of osteoclast-specific genes. Finally, we determined that flavopiridol suppressed RANKL signaling pathway via inhibition of p65 phosphorylation and nuclear translocation of NF-κB. Summary, CDK9 is a potential therapeutic target to prevent osteolysis and osteoporosis by flavopiridol treatment.

Keywords: flavopiridol, CDK9, osteoclast, Bone Resorption, NF-κB

Received: 18 Jan 2018; Accepted: 15 Feb 2018.

Edited by:

Jean-Marie Boeynaems, Free University of Brussels, Belgium

Reviewed by:

Domenico Criscuolo, Genovax S.r.l., Italy
Robert L. Lins, Independent researcher  

Copyright: © 2018 Hu, Chen, Song, Yik, Haudenschild and Fan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD. Shunwu Fan, Sir Run Run Shaw Hospital, Orthopedic surgery department, 3# eastern qingchun road, Hangzhou, China, 11118149@zju.edu.cn