Research Paper Volume 15, Issue 19 pp 10213—10236

Icaritin ameliorates RANKL-mediated osteoclastogenesis and ovariectomy-induced osteoporosis

Jun-ming Huang1,2, *, , Zhe Wang3, *, , Guo-Bin Qi3, *, , Qi Lai2, , A-lan Jiang4, , Yue-Qi Zhang3, , Kun Chen5, , Xiu-Hui Wang1, ,

  • 1 Department of Orthopedics, Shanghai University of Medicine and Health Sciences Affiliated to Zhoupu Hospital, Shanghai, China
  • 2 The Orthopedic Hospital, The First Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
  • 3 Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
  • 4 Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 5 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
* Equal contribution

Received: May 23, 2023       Accepted: August 21, 2023       Published: October 3, 2023
How to Cite

Copyright: © 2023 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


A rapidly aging society and longer life expectancy are causing osteoporosis to become a global epidemic. Over the last five decades, a number of drugs aimed at reducing bone resorption or restoring bone mass have been developed, but their efficacy and safety are limited. Icaritin (ICT) is a natural compound extracted from anti-osteoporosis herb Epimedium spp. and has been shown to inhibit osteoclast differentiation. However, the molecular mechanism by which ICT weaken RANKL-induced osteoclast differentiation has not been completely investigated. Here, we evaluated the anti-osteoclastogenic effect of ICT in vitro and the potential drug candidate for treating osteoporosis in vivo. In vitro study, ICT was found to inhibit osteoclast formation and bone resorption function via downregulating transcription factors activated T cell cytoplasm 1 (NFATc1) and c-fos, which further downregulate osteoclastogenesis-specific gene. In addition, the enhanced mitochondrial mass and function required for osteoclast differentiation was mitigated by ICT. The histomorphological results from an in vivo study showed that ICT attenuated the bone loss associated with ovariectomy (OVX). Based on these results, we propose ICT as a promising new drug strategy for osteoporosis that inhibits osteoclast differentiation.


ICT: icaritin; NFATc1: activated T cell cytoplasm 1; OVX: ovariectomy; CTSK: cathepsin K; MMPs: matrix metalloproteinases; M-CSF: macrophage colony-stimulating factor; RANKL: receptor activator of NF-κB ligand; RANK: receptor activator of NF-κB; α-MEM: minimum essential medium eagle-alpha modification; FBS: fetal bovine serum; TRAP: Tartrate resistant acid phosphatase; DMSO: Dimethyl sulfoxide; PFA: Paraformaldehyde; BMMs: bone marrow macrophages; BV/TV: bone volume/tissue volume; Tb.N: trabecular number; Tb.Th: trabecular thickness; Tb.Sp: trabecular separation; N.Oc/BS: number of osteoclasts normalized to the bone surface; OcS/BS: surface area of osteoclast to bone surface area.