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Yet, the mechanisms mediating the effects of oestrogen on osteoclasts remain unclear. This study aimed to elucidate the early metabolic alteration induced by RANKL, the essential cytokine in osteoclastogenesis and 17\u2010beta\u2010oestradiol (E<jats:sub>2<\/jats:sub>) on osteoclast progenitor cells, using RAW 264.7 macrophage cell line and primary bone marrow\u2010derived macrophages as biological models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This research demonstrated that, in osteoclast precursors, RANKL stimulates complex I activity, oxidative phosphorylation (OXPHOS) and mitochondria\u2010derived ATP production as early as 3\u2009h of exposure. This effect on mitochondrial bioenergetics is associated with an increased capacity to oxidize TCA cycle substrates, fatty acids and amino acids. E<jats:sub>2<\/jats:sub> inhibited all effects of RANKL on mitochondria metabolism. In the presence of RANKL, E<jats:sub>2<\/jats:sub> also decreased cell number and stimulated the mitochondrial\u2010mediated apoptotic pathway, detected as early as 3\u2009h. Further, the pro\u2010apoptotic effects of E<jats:sub>2<\/jats:sub> during osteoclast differentiation were associated with an accumulation of p392S\u2010p53 in mitochondria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings elucidate the early effects of RANKL on osteoclast progenitor metabolism and suggest novel p53\u2010mediated mechanisms that contribute to postmenopausal osteoporosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.14195","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T04:18:10Z","timestamp":1711167490000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Oestradiol and osteoclast differentiation: Effects on p53 and mitochondrial metabolism"],"prefix":"10.1111","volume":"54","author":[{"given":"Adriana","family":"Marques\u2010Carvalho","sequence":"first","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell 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