Eicosapentaenoic acid supplementation modulates the osteoblast/ osteoclast balance in inflammatory environments and protects against estrogen deficiency-induced bone loss in mice

Background: An imbalance of osteoblasts (OBs) and osteoclasts (OCs) in a chronic inflammatory micro-environment is an important pathological factor leading to osteoporosis. Eicosapentaenoic acid (EPA) has been shown to suppress inflammation in macrophages and adipocytes. However, the effect of EPA on OBs and OCs has yet to be fully elucidated. Aims: We explored the roles of EPA in the differentiation of OBs and OCs, as well as the coupling between OBs and OCs in an inflammatory microenvironment. The effects of EPA on estrogen deficiency-induced osteoporosis were also evaluated. Methods: Mouse bone marrow mesenchymal stem cells (mBMSCs) and mouse bone marrow-derived macrophages (mBMMs) were used for in vitro OBs and OCs differentiation. TNF-a was used to create an inflammatory microenvironment. We examined the effects of EPA on osteoblastogenesis in the absence or presence of TNF-a and collect OBs' culture medium as the conditioned medium (CM). Then we examined the effects of EPA and CM on RANKL-induced osteoclastogenesis. The in vivo effects of EPA were determined using an ovariectomized (OVX) mouse model treated with EPA or vehicle. Results: High-dose EPA was shown to promote osteoblastogenesis in an inflammatory environment in vitro, as well as upregulate expression of OBs-specific proteins and genes. ARS and ALP staining also showed that high-dose EPA-treated groups restored mBMSCs' impaired osteogenic capacity caused by TNFa. Mechanistically, EPA suppressed the NF-kB pathway activated by TNF-a in mBMSCs and rescued TNF-a-mediated inhibition of osteoblastogenesis. EPA was also shown to inhibit expression of RANKL and decrease the RANKL/OPG ratio in OBs in an inflammatory environment. CM from TNF-a-stimulated OBs promoted osteoclastogenesis of mBMMs; EPA-treated CM prevented this. In the OVX mouse model, EPA supplementation prevented bone loss in an estrogen deficiency-induced inflammatory environment. Conclusions: EPA was demonstrated for the first time to restore mBMSCs' impaired osteogenic capacity caused by TNFa-induced inflammation and rescue the OBs/OCs balance via regulation of RANKL and OPG expression in OBs. EPA showed a remarkable ability to prevent bone loss in OVX mice, suggesting a potential application of EPA in postmenopausal osteoporosis. & COPY; 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Automated summary

This study found that EPA can promote osteoblast differentiation and regulate the balance between osteoblasts and osteoclasts in an inflammatory environment, thereby preventing osteoporosis. The results show that EPA can inhibit the activation of the NF-kB pathway induced by TNF-a, reduce the expression of RANKL, and inhibit osteoclastogenesis. In addition, the effectiveness of EPA in preventing osteoporosis was also confirmed in an animal model.