Protective Effect of Ciclopirox against Ovariectomy-Induced Bone Loss in Mice by Suppressing Osteoclast Formation and Function.

Hye Jung Ihn,Eui Kyun Park,Jiwon Lim,Jong-Sup Bae,Kiryeong Kim,Yong Chul Bae,Soomin Lim,Moon-Chang Baek,Sang-Hyeon Nam,Tae Hoon Kim,Jung-Eun Kim,Su Jeong Lee

doi:10.3390/ijms22158299

Abstract

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.

Highlights

To verify the therapeutic potential of ciclopirox, we examined its effect on osteoclast differentiation and function and elucidated the molecular mechanism through which ciclopirox attenuates osteoclastogenesis and bone resorption
Macrophage colony-stimulating factor (M-CSF) and RANKL promoted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs); the addition of ciclopirox significantly reduced osteoclast formation from bone marrow macrophages (BMMs) (Figure 1A)
The number of TRAP-positive MNCs observed 4 days after treatment with 2.5 μM of ciclopirox was decreased by 97.5% compared with the vehicle-treated control, and the inhibitory effect of

Summary

Introduction

Bone homeostasis is controlled by coordinating the functions of bone cells, including osteoblasts and osteoclasts, in response to various stimuli. Osteoblasts are primarily responsible for the synthesis of the bone matrix, whereas osteoclasts are capable of degrading mineralized tissue by producing protons and proteolytic enzymes [1]. Disruption of the balance between the activities of these bone cells resulting from increased osteoclastic bone resorption can cause osteoporosis, periprosthetic osteolysis, and other bone diseases [2]. Osteoporosis is recognized as a serious health problem because of severe complications, including bone fractures. Antiresorptive drugs are used, which improve bone strength; several adverse events have been reported [3,4], which indicates a need for alternative agents

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Conclusion