Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo.

Qiang Xu,Hongxian Fan,Guoming Xia,Bin Zhang,Min Dai,Xuqiang Liu,Haibo Zhan,Guiping Chen,Meisong Zhu,Huaen Xu

doi:10.3389/fphar.2021.682541

Abstract

Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor β-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.

Highlights

The skeletal system’s metabolic pattern is primarily controlled by systemic hormones or local regulating factors through the control of osteoblastic bone formation and osteoclastic bone resorption (Sims and Gooi, 2008)
To rule out that the reduction in mature osteoclast formation was due to the cytotoxicity and proliferation effects of celastrol, we investigated the effects of celastrol on bone marrow monocyte/macrophage (BMM) viability using the CCK-8 assay
Our results showed that celastrol was not cytotoxic and had no inhibitory effect on the viability of BMMs at doses

Summary

Introduction

The skeletal system’s metabolic pattern is primarily controlled by systemic hormones or local regulating factors through the control of osteoblastic bone formation and osteoclastic bone resorption (Sims and Gooi, 2008). The increased number and activity of osteoclasts can result in diseases associated with excessive bone resorption, such as periprosthetic osteolysis and osteoporosis (D’Amico and Roato, 2012). Evidence suggests that transforming growth factor β-activated kinase 1 (TAK1) is referred in RANKL signaling pathways and demonstrates that the TRAF6-TAB2-TAK1 complex is required for the activation of NF-κB (Zhang et al, 2017). As these signaling mechanisms are active, transcription factors such as c-fos (Grigoriadis et al, 1994) and nucle-ar factor of activated T cells c1 (NFATc1) (Takayanagi et al, 2002) are upregulated and activated, resulting in osteoclastogenesis. Recent studies have highlighted the increasing popularity of the potential pharmacological activities of natural compounds and their derivatives for applications in human diseases (An et al, 2016)

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Conclusion