Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Okanin attenuates ovariectomy-induced bone loss in mice model through inhibition of IKKβ-mediated NF-κB p65 phosphorylation.
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Shi Kai, Wang Ying-Jian, Wang Shaoming, Guan Zhenhong, Li Man, Zhao Ya-Nan, Sun Wan-Chun
Аннотация
BACKGROUND: Excessive activation of osteoclasts can lead to excessive bone resorption, thereby causing bone loss diseases. Okanin, a flavonoid derived from Coreopsis tinctoria, has been reported to possess antibacterial, anti-inflammatory and antioxidant activities, and has therapeutic effects on cerebral ischemia. Although okanin is known for other biological activities, its role in bone metabolism has not been clearly elucidated before.
PURPOSE: In the present study, we evaluated the effects of okanin on osteoclast formation and function through in vitro assays, and further assessed its capacity to mitigate bone loss in a murine model of ovariectomy (OVX)-induced osteoporosis in vivo.
STUDY DESIGN: We employed a combination of in vitro cell-based assays and an in vivo ovariectomy (OVX)-induced osteoporosis mouse model to systematically assess okanin's bone-protective effects and underlying mechanisms.
METHODS: In vitro, bone marrow macrophages (BMMs) were treated with okanin (1.25-20 μM) during RANKL-induced osteoclast differentiation. Key endpoints included TRAP-positive multinucleated cell formation, F-actin ring integrity, resorption pit activity, and expression of osteoclastogenic markers (c-Fos, NFATc1) and signaling molecules (IKKβ, NF-κB p65). In silico molecular docking analyzed okanin's interaction with IKKα/β. In vivo, OVX mice were administered okanin (2 or 10 mg/kg, i.p.) for 8 weeks, followed by micro-CT, histological, and TRAP staining analyses of femurs to assess bone microarchitecture and osteoclast activity.
RESULTS: In vitro, okanin dose-dependently inhibited RANKL-induced osteoclast differentiation and disrupted F-actin ring formation without cytotoxicity. It downregulated c-Fos, NFATc1, and their target genes (TRAP, MMP-9, Atp6v0d2), while selectively suppressing IKKβ phosphorylation and NF-κB p65 activation (without affecting MAPK pathways or IKKα). Okanin also blunted RANKL-induced Blimp1 upregulation and preserved NFATc1 inhibitors (Bcl6, MafB, IRF8). In vivo, okanin dose-dependently preserved trabecular bone architecture in OVX mice, improving bone volume fraction (BV/TV), trabecular number (Tb.N), and thickness (Tb.Th), while reducing osteoclast numbers.
CONCLUSION: In conclusion, these findings establish okanin as a novel bone-protective agent that inhibits osteoclastogenesis through a distinct mechanism involving selective IKKβ/NF-κB inhibition, thereby attenuating OVX-induced bone loss. This specificity distinguishes it from other compounds and highlights its promise as a lead candidate for development as a functional food supplement or therapeutic agent for osteoporosis.
PURPOSE: In the present study, we evaluated the effects of okanin on osteoclast formation and function through in vitro assays, and further assessed its capacity to mitigate bone loss in a murine model of ovariectomy (OVX)-induced osteoporosis in vivo.
STUDY DESIGN: We employed a combination of in vitro cell-based assays and an in vivo ovariectomy (OVX)-induced osteoporosis mouse model to systematically assess okanin's bone-protective effects and underlying mechanisms.
METHODS: In vitro, bone marrow macrophages (BMMs) were treated with okanin (1.25-20 μM) during RANKL-induced osteoclast differentiation. Key endpoints included TRAP-positive multinucleated cell formation, F-actin ring integrity, resorption pit activity, and expression of osteoclastogenic markers (c-Fos, NFATc1) and signaling molecules (IKKβ, NF-κB p65). In silico molecular docking analyzed okanin's interaction with IKKα/β. In vivo, OVX mice were administered okanin (2 or 10 mg/kg, i.p.) for 8 weeks, followed by micro-CT, histological, and TRAP staining analyses of femurs to assess bone microarchitecture and osteoclast activity.
RESULTS: In vitro, okanin dose-dependently inhibited RANKL-induced osteoclast differentiation and disrupted F-actin ring formation without cytotoxicity. It downregulated c-Fos, NFATc1, and their target genes (TRAP, MMP-9, Atp6v0d2), while selectively suppressing IKKβ phosphorylation and NF-κB p65 activation (without affecting MAPK pathways or IKKα). Okanin also blunted RANKL-induced Blimp1 upregulation and preserved NFATc1 inhibitors (Bcl6, MafB, IRF8). In vivo, okanin dose-dependently preserved trabecular bone architecture in OVX mice, improving bone volume fraction (BV/TV), trabecular number (Tb.N), and thickness (Tb.Th), while reducing osteoclast numbers.
CONCLUSION: In conclusion, these findings establish okanin as a novel bone-protective agent that inhibits osteoclastogenesis through a distinct mechanism involving selective IKKβ/NF-κB inhibition, thereby attenuating OVX-induced bone loss. This specificity distinguishes it from other compounds and highlights its promise as a lead candidate for development as a functional food supplement or therapeutic agent for osteoporosis.