Oestradiol and osteoclast differentiation: Effects on p53 and mitochondrial metabolism

Eur J Clin Invest. 2024 Jun;54(6):e14195. doi: 10.1111/eci.14195. Epub 2024 Mar 22.

Abstract

Background: Oestrogen deficiency increases bone resorption, contributing to osteoporosis development. 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-beta-oestradiol (E2) on osteoclast progenitor cells, using RAW 264.7 macrophage cell line and primary bone marrow-derived macrophages as biological models.

Results: This research demonstrated that, in osteoclast precursors, RANKL stimulates complex I activity, oxidative phosphorylation (OXPHOS) and mitochondria-derived ATP production as early as 3 h of exposure. This effect on mitochondrial bioenergetics is 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 3 h. Further, the pro-apoptotic effects of E2 during osteoclast differentiation were associated with an accumulation of p392S-p53 in mitochondria.

Conclusions: These findings elucidate the early effects of RANKL on osteoclast progenitor metabolism and suggest novel p53-mediated mechanisms that contribute to postmenopausal osteoporosis.

Keywords: bone; mitochondria; oestradiol; osteoporosis; p53.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation* / drug effects
  • Estradiol* / pharmacology
  • Macrophages / metabolism
  • Mice
  • Mitochondria* / metabolism
  • Osteoclasts* / drug effects
  • Osteoclasts* / metabolism
  • Oxidative Phosphorylation / drug effects
  • RANK Ligand / metabolism
  • RAW 264.7 Cells
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Adenosine Triphosphate
  • Estradiol
  • RANK Ligand
  • Tumor Suppressor Protein p53

Associated data

  • RefSeq/NC_000077
  • RefSeq/NC_010339
  • RefSeq/NC_005089
  • RefSeq/NC_000074
  • RefSeq/NC_000068
  • RefSeq/NM_000369
  • RefSeq/NC_000072
  • RefSeq/NC_000084
  • RefSeq/NC_000073
  • RefSeq/NC_000076