Ergothioneine Attenuates Ovariectomy-Induced Bone Loss in Association With Reduced Oxidative Stress and Enhanced Type H Vessel-Related Angiogenesis

Background: Ergothioneine (EGT) has been reported to alleviate estrogen deficiency-induced osteoporosis, but whether this protection is accompanied by alterations in the bone microvasculature accompany this protection remain unknown. Therefore, this study aimed to examine the effects of EGT in ovariectomized (OVX) mice, with particular attention to type H vessels. Methods: A total of 18 female C57BL/6J mice were randomly assigned to the sham, OVX, and OVX + EGT groups (n = 6 each). EGT was initiated 24 h after OVX and administered for 12 weeks. Femoral structure was evaluated using micro-computed tomography, hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence. Meanwhile, serum assays were used to characterize bone turnover and oxidative stress. In addition, mouse bone-derived type H endothelial cells were exposed to EGT. The localization of organic cation transporter novel type 1 (OCTN1) was examined by immunofluorescence. Angiogenic activity was measured in Matrigel, while OCTN1 gene and protein expression were assessed by reverse-transcription quantitative polymerase chain reaction and Western blotting, respectively. Results: In OVX mice, EGT increased bone mineral density and improved trabecular microarchitecture. Serum superoxide dismutase activity and glutathione concentrations were higher after EGT administration, whereas advanced oxidation protein products and malondialdehyde levels were lower. Bone sections also showed a larger CD31+ vascular area, more osterix-positive (Osx+) osteogenic cells, and a closer spatial association between these signals. EGT increased OCTN1 expression in vitro and promoted angiogenesis. Conclusions: Early administration of EGT alleviated OVX-induced bone loss. This effect may be linked to reduced oxidative stress and enhanced angiogenesis related to type H vessels.