Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Isoeugenol suppression of osteoporosis by modulating macrophage M1 Polarization via p38 MAPK and arachidonic acid metabolism pathways.
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Chen Fancheng, Geng Wei, Wang Yifei, Lai Xiaowen, Liu Bingli, Huang Xiaowei
Аннотация
BACKGROUND: Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by accelerated bone loss, primarily driven by excessive osteoclast activity. The role of immune-bone interactions, particularly macrophage polarization, in osteoporosis pathogenesis has gained increasing attention. Isoeugenol (IEG), a natural phenolic compound, has demonstrated anti-inflammatory properties, but its effects on bone metabolism and macrophage polarization remain unclear.
PURPOSE: To investigate the therapeutic effect of IEG on ovariectomy (OVX)-induced osteoporosis and to elucidate the underlying mechanisms, with a focus on its regulation of macrophage M1 polarization.
STUDY DESIGN: In vitro, LPS/IFN-γ-stimulated RAW264.7 macrophages were used to model M1 polarization. In vivo, an OVX-induced mouse model of postmenopausal osteoporosis was established to evaluate the effect of IEG on bone microstructure and macrophage polarization.
RESULTS: In vitro, IEG significantly inhibited LPS/IFN-γ induced M1 macrophage polarization, downregulating the expression of M1 markers and the secretion of pro-inflammatory cytokines. Conditioned medium from IEG-treated macrophages inhibited the capacity to promote osteoclast differentiation. Mechanistically, IEG exerted its effects by inhibiting p38 MAPK phosphorylation. This suppression of p38 signaling acted upstream to reduce the phosphorylation of cytosolic phospholipase A₂ (cPLA₂) and consequently reprogrammed arachidonic acid (AA) metabolism. The critical role of this p38-AA axis was confirmed by a rescue experiment, where exogenous AA supplementation reversed the inhibitory effects of IEG on M1 polarization. In vivo, IEG treatment ameliorated OVX-induced bone loss, improved trabecular microstructure, and reduced the proportion of CD86⁺ M1 macrophages in the bone marrow.
CONCLUSION: Isoeugenol demonstrated great potential as a novel therapeutic agent that ameliorated osteoporosis by sequentially inhibiting the macrophage p38 MAPK-AA metabolic axis, thereby reprogramming osteoimmune homeostasis.
PURPOSE: To investigate the therapeutic effect of IEG on ovariectomy (OVX)-induced osteoporosis and to elucidate the underlying mechanisms, with a focus on its regulation of macrophage M1 polarization.
STUDY DESIGN: In vitro, LPS/IFN-γ-stimulated RAW264.7 macrophages were used to model M1 polarization. In vivo, an OVX-induced mouse model of postmenopausal osteoporosis was established to evaluate the effect of IEG on bone microstructure and macrophage polarization.
RESULTS: In vitro, IEG significantly inhibited LPS/IFN-γ induced M1 macrophage polarization, downregulating the expression of M1 markers and the secretion of pro-inflammatory cytokines. Conditioned medium from IEG-treated macrophages inhibited the capacity to promote osteoclast differentiation. Mechanistically, IEG exerted its effects by inhibiting p38 MAPK phosphorylation. This suppression of p38 signaling acted upstream to reduce the phosphorylation of cytosolic phospholipase A₂ (cPLA₂) and consequently reprogrammed arachidonic acid (AA) metabolism. The critical role of this p38-AA axis was confirmed by a rescue experiment, where exogenous AA supplementation reversed the inhibitory effects of IEG on M1 polarization. In vivo, IEG treatment ameliorated OVX-induced bone loss, improved trabecular microstructure, and reduced the proportion of CD86⁺ M1 macrophages in the bone marrow.
CONCLUSION: Isoeugenol demonstrated great potential as a novel therapeutic agent that ameliorated osteoporosis by sequentially inhibiting the macrophage p38 MAPK-AA metabolic axis, thereby reprogramming osteoimmune homeostasis.