Nicorandil Inhibits Osteoclast Formation Base on NF-κB and p-38 MAPK Signaling Pathways and Relieves Ovariectomy-Induced Bone Loss.

Zhenxing Yu,Wang Lin,Yichuan Pang,Weizhong Guo,Xiongwei Lu,Shenggui Xu,Xiankun Cao,Wenxin He,Chengshou Lin,Zhiqian Chen

doi:10.3389/fphar.2021.726361

Zhenxing Yu, Wang Lin + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2021.726361

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Abstract

Osteolytic bone disorders are characterized by an overall reduction in bone mineral density which enhances bone ductility and vulnerability to fractures. This disorder is primarily associated with superabundant osteoclast formation and bone resorption activity. Nicorandil (NIC) is a vasodilatory anti-anginal drug with ATP-dependent potassium (KATP) channel openings. However, NIC is adopted to manage adverse cardiovascular and coronary events. Recent research has demonstrated that NIC also possesses anti-inflammatory peculiarity through the regulation of p38 MAPK and NF-κB signaling pathways. Both MAPK and NF-κB signaling pathways play pivotal roles in RANKL-induced osteoclast formation and bone resorption function. Herein, we hypothesized that NIC may exert potential biological effects against osteoclasts, and revealed that NIC dose-dependently suppressed bone marrow macrophage (BMM) precursors to differentiate into TRAP + multinucleated osteoclasts in vitro. Furthermore, osteoclast resorption assays demonstrated anti-resorptive effects exhibited by NIC. NIC had no impact on osteoblast differentiation or mineralization function. Based on Biochemical analyses, NIC relieved RANKL-induced ERK, NF-κB and p38 MAPK signaling without noticeable effects on JNK MAPK activation. However, the attenuation of NF-κB and p38 MAPK activation was sufficient to hamper the downstream induction of c-Fos and NFATc1 expression. Meanwhile, NIC administration markedly protected mice from ovariectomy (OVX)-induced bone loss through in vivo inhibition of osteoclast formation and bone resorption activity. Collectively, this work demonstrated the potential of NIC in the management of osteolytic bone disorders mediated by osteoclasts.

Highlights

With the ageing population, numerous bone-related diseases and morbidity including osteoporosis are increasingly becoming a worldwide public health concern
Thereafter, macrophage colony-stimulating factor (M-CSF)-dependent bone marrow macrophage (BMM) were stimulated with RANKL without or with suggested concentrations of NIC for 5 days followed by the assessment of multinucleated osteoclast formation through staining for tartrate-resistant acid phosphatase (TRAP) activity
Perturbations in the bone homeostasis balance can lead to excessive formation of osteoclast and bone resorption which transpire to many osteolytic bone diseases such as osteoporosis (Kular et al, 2012; Kim et al, 2014; Langdahl et al, 2016; Katsimbri, 2017; Myneni and Mezey, 2017; Zhu et al, 2017; Yedavally-Yellayi et al, 2019b)

Summary

Introduction

Numerous bone-related diseases and morbidity including osteoporosis are increasingly becoming a worldwide public health concern. This is attributed to the substantial bone-associated morbidities and mortality, associated socio-economic and healthcare costs (Harvey et al, 2010; Rachner et al, 2011; Yedavally-Yellayi et al, 2019a). Excessive osteoclast-mediated bone resorption underlies the pathological manifestations of bone loss characterized by thinning of cortical bones, reduction in trabecular bone mass and an overall reduction in bone mineral density. These events contribute to an overall deterioration in bone microarchitecture and high risks of bone fractures (Del Puente et al, 2015). Pharmacological chemicals capable of inhibiting RANKL-RANK signaling transmission have great potential in the therapeutical management of osteolytic diseases

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