Flavopiridol Protects Bone Tissue by Attenuating RANKL Induced Osteoclast Formation.

Zi’Ang Hu,Dominik R Haudenschild,Shunwu Fan,Lijiang Song,Yilei Chen,Jasper H N Yik

doi:10.3389/fphar.2018.00174

Abstract

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 (BMMs). 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.

Highlights

Bone tissue homeostasis is maintained by the dynamic balance between osteoblastic bone formation and osteoclastic bone resorption (Seeman and Delmas, 2006)
Given the well-known role of NF-κB in inflammation and in RANKL signaling in osteoclast formation, we investigated the roles of cyclin-dependent kinase 9 (CDK9) in osteoclast function, using two in vivo mouse models of bone remodeling: (1) acute titanium particles-induced osteolysis, and (2) chronic estrogen deficiency-induced osteoporosis
We evaluated the effects of flavopiridol treatment using two animal models with bone loss induced by Ti-particles or ovariectomy

Summary

Introduction

Bone tissue homeostasis is maintained by the dynamic balance between osteoblastic bone formation and osteoclastic bone resorption (Seeman and Delmas, 2006). This balance is vulnerable to influence by physical, endocrine and paracrine stimuli under various physiological and pathological conditions. Recent studies have demonstrated that the resorption or remodeling of bone tissue mainly depends on the differentiation of osteoclasts (Boyce et al, 2009), which is regulated by two essential cytokines, namely macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) (Abu-Amer, 2013; Sucur et al, 2014). M-CSF plays a central role in directing hematopoietic stem cells into the monocyte/macrophage lineage, and in up-regulating RANK expression, which is required for osteoclast differentiation. RANKL is a transmembrane protein that belongs to the tumor necrosis factor (TNF) superfamily that is closely associated with both acute and chronic inflammation (Boyce and Xing, 2008; Xing et al, 2012)

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