The effect of estradiol during the early stages of osteoclast differentiation is associated with the accumulation of phosphorylated p53 in mitochondria and the inhibition of mitochondrial metabolism.
Carvalho, A. M.; Silva, B.; Pereira, F. B.; Kim, H.-N.; Almeida, M.; Sardao, V. A.
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Estrogen deficiency increases bone resorption and is a major contributor to osteoporosis. However, the molecular mechanisms mediating the effects of estrogen on osteoclasts remain unclear. This study aimed at elucidating the early metabolic effects of RANKL - the essential cytokine for osteoclastogenesis - and 17-beta-estradiol (E2) on osteoclast progenitor cells, using RAW 264.7 macrophage cell line and bone marrow-derived macrophages as biological models. RANKL stimulated complex I activity, oxidative phosphorylation (OXPHOS), and mitochondria-derived ATP production, as early as 3 to 6 h. This up-regulation of mitochondrial bioenergetics was associated with an increased capacity to oxidize TCA cycle substrates, fatty acids, and amino-acids. E2 inhibited all effects of RANKL on mitochondria metabolism. In the presence of RANKL, E2 also decreased cell number and stimulated the mitochondrial-mediated apoptotic pathway, detected as early as 3h. Surprisingly, the pro-apoptotic effects of E2 were associated with an accumulation of p392S-p53 in mitochondria. These findings elucidate early effects of RANKL on osteoclast progenitor metabolism and suggest novel p53-mediated mechanisms that contribute to postmenopausal osteoporosis.
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