Ellagic acid protects ovariectomy‐induced bone loss in mice by inhibiting osteoclast differentiation and bone resorption

Abstract

Osteoporosis is a devastating disease that features reduced bone quantity and microstructure, which causes fragility fracture and increases mortality, especially in the aged population. Due to the long-term side-effects of current drugs for osteoporosis, it is of importance to find other safe and effective medications. Ellagic acid (EA) is a phenolic compound found in nut galls, plant extracts, and fruits, and exhibits antioxidant and antineoplastic effects. Here, we showed that EA attenuated the formation and function of osteoclast dose-dependently. The underlying mechanism was further discovered by western blot, immunofluorescence assay, and luciferase assay, which elucidated that EA suppressed osteoclastogenesis and bone resorption mainly through attenuating receptor activator of nuclear factor-κB (NF-κB) ligand-induced NF-κB activation and extracellular signal-regulated kinase signaling pathways, accompanied by decreased protein expression of nuclear factor of activated T-cells calcineurin-dependent 1 and c-Fos. Moreover, EA inhibits osteoclast marker genes expression including Dc-stamp, Ctsk, Atp6v0d2, and Acp5. Intriguingly, we also found that EA treatment could significantly protect ovariectomy-induced bone loss in vivo. Conclusively, this study suggested that EA might have the therapeutic potentiality for preventing or treating osteoporosis. K E Y W O R D S ellagic acid, ERK, NF-κB, osteoclast, osteoporosis, RANKL Xixi Lin and Guixin Yuan contributed equally to this work.

Ellagic Acid Exerts Beneficial Effects on Hyperuricemia by Inhibiting Xanthine Oxidase and NLRP3 Inflammasome Activation

“…Notably, EA downregulated the expression levels of TNF-α, ASC, p-p65, and other NLRP3 inflammasome-related proteins. These observations suggested that the regulatory effects of EA on hyperuricemia are related to its ability to inhibit the NLRP3 signaling pathway, similar to that reported for EA in protecting bone loss in mice through the attenuation of the NF-κB signaling pathway . Analysis of tissue morphology further showed that EA can protect against liver and renal damage, at least partially (Figure ).…”

“…These observations suggested that the regulatory effects of EA on hyperuricemia are related to its ability to inhibit the NLRP3 signaling pathway, similar to that reported for EA in protecting bone loss in mice through the attenuation of the NF-κB signaling pathway. 40 Analysis of tissue morphology further showed that EA can protect against liver and renal damage, at least partially (Figure 6). Combined, these results demonstrated that the attenuating effects of EA on hyperuricemia-induced hepatorenal injury are likely mediated through directly inhibiting the NLRP3 pathway.…”

Phoenix dactilyfera L. Pits Extract Restored Bone Homeostasis in Glucocorticoid-Induced Osteoporotic Animal Model through the Antioxidant Effect and Wnt5a Non-Canonical Signaling

“…Furthermore, vanillic and syringic acids [119], resveratrol [115,120], catechins [121], caffeic acid [77], and chlorogenic acid [122] were found to decrease the number of RANKL-induced osteoclastogenesis by reducing RANKL/OPG ratio supported by the reduced ACP and TRAP activities and/or gene expression level in osteoporotic rat models and cells. Moreover, chlorogenic [123] and ellagic acids [124] stimulated osteoblast precursors proliferation and differentiation in ovariectomized animal models and suppressed RANKL-induced osteoclastogenesis through suppressing p38-MAPK signaling pathways. Furthermore, rutin [125] and P-coumaric acid [126] improved bone histomorphometry and biochemical markers of bone turnover associated with reduced osteoclastic activity, increased bone mass/body mass ratio and bone mineral mass/body mass ratio in ovariectomized mice.…”

Mogrol Attenuates Osteoclast Formation and Bone Resorption by Inhibiting the TRAF6/MAPK/NF-κB Signaling Pathway In vitro and Protects Against Osteoporosis in Postmenopausal Mice

“…As a result, there is still a need to discover new medications that are free of these adverse effects and could be applied long-term. Recently, natural plant extracts have been an attractive alternative drug for osteoporosis due to their low toxicity ( Zhan et al, 2019 ; Lin et al, 2020 ; Wang et al, 2021 ). Our study showed that mogrol, an aglycon of mogroside extracted from Siraitia grosvenorii (Swingle), has an inhibitory impact on osteoclast differentiation and function in vitro and protects against bone mass loss in postmenopausal mice.…”