BCI Suppresses RANKL-Mediated Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss

Chenhui Cai,Hao Qiu,Tongwei Chu,Xu Hu,Sizhen Yang,Wenhui Hu,Yiyun Qiu,Rujie Wang,Min Ma,Ying Zhang

doi:10.3389/fphar.2021.772540

Chenhui Cai, Hao Qiu + Show 8 more

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https://doi.org/10.3389/fphar.2021.772540

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Abstract

Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory due to detrimental side effects. BCI hydrochloride (BCI), a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, is associated with multiple cellular functions, including inhibiting tumor growth and macrophage inflammation; however, its role in regulating osteoclast differentiation remains unknown. Here, we revealed that treatment with BCI attenuated RANKL-mediated osteoclast differentiation in vitro and alleviated ovariectomy-induced osteoporosis without obvious toxicity. Specifically, BCI disrupted F-actin ring formation and bone-resorption activity and decreased osteoclast-specific gene and protein levels in a dose-dependent manner. KEGG pathway analysis, GSEA based on transcriptome sequencing, and western blot results suggested that BCI inhibited RANKL-induced osteoclastogenesis by restraining STAT3 and NF-κB signaling and attenuating NF-κB/p65 interaction with NFATc1. These results revealed that BCI treatment prevented postmenopausal osteoporosis and might represent an effective approach for treating osteoporosis.

Highlights

Osteoporosis is a common and frequent skeletal disorder due to an imbalance in bone remodeling associated with excessive osteoclast activity and inadequate osteoblast generation (Henriksen et al, 2011; Rachner et al, 2011)
BCI hydrochloride (BCI) Suppresses Osteoclastogenesis interaction on the surface of preosteoclasts leads to activation of a range of downstream signals, including those related to nuclear factor-kappaB (NF-κB), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3), that initiate osteoclast activation, differentiation, and function (Kim et al, 2017)
We subsequently confirmed that BCI suppressed dualspecificity phosphatase 6 (DUSP6) protein expression in RAW264.7 cells and Bone marrow monocytes/macrophages (BMMs) during RANKL-mediated osteoclast differentiation (Figure 1F)

Summary

Introduction

Osteoporosis is a common and frequent skeletal disorder due to an imbalance in bone remodeling associated with excessive osteoclast activity and inadequate osteoblast generation (Henriksen et al, 2011; Rachner et al, 2011). New agents targeting osteoclast boneresorption activity or osteoblastic bone formation, including bisphosphonates, calcitonin, denosumab, selective estrogen receptor modulators, and teriparatide, have been widely developed, explored, and utilized to prevent and treat osteoporosis (Khalili et al, 2012; Leder et al, 2015). Most of these therapeutic approaches lead to serious side effects, which discourage their long-term use and patient compliance (Li et al, 2019). There is an urgent need to develop alternative approaches to treating osteoporosis with improved effectiveness and lower toxicity

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