2. Academic Validation
  3. Onc201 reduces osteoclastogenesis and prevents ovariectomy-induced bone loss via inhibiting RANKL-induced NFATc1 activation and the integrin signaling pathway

Onc201 reduces osteoclastogenesis and prevents ovariectomy-induced bone loss via inhibiting RANKL-induced NFATc1 activation and the integrin signaling pathway

  • Eur J Pharmacol. 2022 May 15;923:174908. doi: 10.1016/j.ejphar.2022.174908.
Liwei Wu 1,  Jiamin Liang 1,  Jing Li 1,  Yang Xu 2,  Junchun Chen 1,  Yuangang Su 1,  Yansi Xian 1,  Jiyong Wei 3,  Jiake Xu 4,  Jinmin Zhao 5,  Qian Liu 6,  Yuan Yang 7
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China; Collaborative Innovation Center of Regenerative Medicine and Medical Biological Resources Development and Application, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
  • 2 Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
  • 3 Department of Orthopedics, The First People's Hospital of Nanning, Nanning, Guangxi, 530016, People's Republic of China.
  • 4 School of Biomedical Sciences, University of Western Australia, Perth, WA, 6009, Australia.
  • 5 Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China; Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
  • 6 Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China. Electronic address: luoboqian@hotmail.com.
  • 7 Department of Orthopedics, Kaiyuan Langdong Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, Guangxi, 530028, People's Republic of China; Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China. Electronic address: yangy062@sina.com.
PMID: 35405113 DOI: 10.1016/j.ejphar.2022.174908
Abstract

Osteoporosis is an osteolytic disease with a disrupted balance between the resorption and formation of bone as well as bone microstructure degeneration, leading to bone loss and increased fracture risk, which greatly affects patients' quality of life. Currently, inhibition of osteoclast bone resorption remains the mainstream treatment for osteoporosis. Onc201, a new compound, induces the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and has an efficient Anticancer effect in clinical trials. However, its effects on osteolytic disease and the mechanism of action are unclear. We examined the effect of Onc201 on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts via Cell Counting Kit-8, bone resorption assay, luciferase reporter assay, immunofluorescence staining, calcium ion intensity assay and employed an ovariectomy model to investigate the effect of Onc201 on osteoporosis in the mice. Results showed that Onc201 inhibited the function and formation of osteoclasts induced by RANKL in a manner that was dependent on time and concentration, and did not cause cytotoxicity. Mechanistically, Onc201 inhibited osteoclast-relevant genes and NFATc1 expression, the main transcriptional regulatory factor of the formation of osteoclasts induced by RANKL; meanwhile, downregulating the expressions of the osteoclast Cytoskeleton key signal molecules Integrin αvβ3, focal adhesion kinase (FAK), c-Src, and spleen-associated tyrosine kinase (Syk). In addition, Onc201 had a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency, which is consistent with the in vitro results. Our findings suggest that the new small-molecular compound Onc201 has the potential to prevent osteoclast-related osteolytic diseases.

Keywords

Integrin αvβ3; NFATc1; Onc201; Osteoclast.

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