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. 2025 Dec 12:2025:5715332.
doi: 10.1155/mi/5715332. eCollection 2025.

Gut-Bone Axis Mediates Exercise Modality-Dependent Suppression of Inflammatory Osteoclastogenesis in Ovariectomy-Induced Bone Loss

Yucheng Gao  1   2   3   4   5 , Hao Wang  1   2   3   4   5 , Liu Shi  1   2   3   4   5 , Mumin Cao  1   2   3   4   5 , Xiaoyu Liu  1   2   3   4   5 , Yuanwei Zhang  6 , Xiangxu Chen  1   2   3   4   5 , Yijun Rong  5 , Bowen Han  5 , Panpan Lu  1   2   3   4   5 , Guangchun Dai  1   2   3   4   5 , Wenbin Fan  1   2   3   4   5 , Yunfeng Rui  1   2   3   4   5 , Yingjuan Li  4   7
Affiliations

Gut-Bone Axis Mediates Exercise Modality-Dependent Suppression of Inflammatory Osteoclastogenesis in Ovariectomy-Induced Bone Loss

Yucheng Gao et al. Mediators Inflamm. .

Abstract

Exercise is crucial for postmenopausal osteoporosis (PMOP) management, yet the comparative efficacy of different exercise modalities and the underlying mechanisms remain unclear. This study investigated the differential effects of distance-matched high-intensity interval training (HIIT) and moderate-intensity continuous exercise (MICE) on ovariectomy (OVX)-induced osteoporosis (OP) in mice. After 12 weeks of training, micro-CT analysis revealed that MICE, but not HIIT, significantly attenuated OVX-induced bone loss and microstructural deterioration. Crucially, only MICE suppressed osteoclastogenesis and reduced proinflammatory factors (interleukin [IL]-6, IL-1β, and tumor necrosis factor-alpha [TNF-α]) expression in the femur, serum, and colon. Mechanistically, MICE uniquely restored gut microbiota (GM) diversity, mitigated dysbiosis, and enhanced intestinal barrier integrity by upregulating the expression of tight junction proteins (TJPs; ZO-1, occludin, and claudin-1), thereby reducing systemic inflammation. In contrast, HIIT failed to ameliorate GM imbalance and intestinal permeability. Our findings demonstrate that the protective effect of MICE on OVX-induced OP is mediated through the gut-bone axis by modulating GM, repairing the intestinal barrier, and suppressing inflammatory osteoclast activation. This study provides novel evidence that the benefits of exercise on PMOP are modality-dependent, highlighting MICE as a superior strategy and offering mechanistic insights for optimizing exercise prescriptions.

Keywords: bone loss; exercise; gut microbiota; ovariectomy; postmenopausal osteoporosis.

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Conflict of interest statement

The authors declare no conflicts of interest.

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