Obacunone inhibits RANKL/M-CSF-mediated osteoclastogenesis by suppressing integrin- FAK-Src signaling. (April 2023)

• Record Type: Journal Article
• Authors: Hu, Huimin; Wang, Xiaodong; Huang, Yansheng; He, Baorong; Zhu, Jinwen; Sun, Kai; Deng, Chaoyang; Guo, Yunshan; Hao, Dingjun; Jian, Bin
• Is Part Of: Cytokine. Volume 164(2023)
• Publication Date: 2023-04
• Subjects: Obacunone -- Osteoclast differentiation -- Integrin -- FAK-Src -- Osteoporosis; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2023.156134
• Languages: English
• ISSNs: 1043-4666

Abstract

Abstract: Disrupted osteoblastogenesis or aberrant activation of osteoclastogenesis usually results in the break of bone homeostasis thus causing bone-associated diseases like osteoporosis. Obacunone, as a natural compound present in citrus fruits, has been demonstrated for various biological activities including anti-cancer and anti-inflammatory properties. However, the role of obacunone in regulating osteoclastogenesis has not been elucidated so far. Here, using in vitro cell models of RANKL (Receptor activator of nuclear factor-kB ligand) and M-CSF (Macrophage-colony-stimulating factor)-induced osteoclastogenesis, we showed that obacunone inhibited osteoclast differentiation in RAW264.7 cells and bone marrow macrophages (BMMs), as evidenced by obacunone dose-dependent reduction in numbers of osteoclasts and downregulated expressions of osteoclastogenesis-associated key genes. The anti-osteoclastic properties of obacunone were associated with downregulated expressions of Integrin α1 and attenuated activation of Focal adhesion kinase (FAK) and Steroid receptor coactivator (Src) signaling. Functional Integrin α1 blockade or FAK-Src inhibition suppressed RANKL/M-CSF-induced osteoclastogenesis, while Integrin α1 overexpression or FAK/Src activation partially attenuated obacunone's effects on suppressing RANKL/M-CSF-induced osteoclast differentiation. Furthermore, in vivo administration of obacunone displayed super therapeutic effects in attenuating ovariectomy-induced bone loss in mice, as indicated by decreases in serum biomarkers of bone turnover, restoring of femur fracture maximum force, and reversing of the worsened bone-related parameters in ovariectomized animals. Taken together, these findings demonstrate that obacunone has pharmacological activities to suppress osteoclast differentiation through modulating the Integrin-FAK-Src pathway, and suggest that obacunone is a therapeutic candidate for the treatment and prevention of bone diseases such as osteoporosis.