Oestrogen-mediated control of the bone marrow microenvironment

Abstract

The bone microenvironment (BM) is highly heterogeneous and is altered significantly during our lifespan. Blood vessels in the bone provide specialised niches that support processes such as osteogenesis, haematopoiesis and adipogenesis. The function of the female hormone, oestrogen has been attributed to bone remodelling during puberty, pregnancy, and menopause. However, the role that oestrogen signalling plays in the bone endothelium and its subsequent changes in the bone microenvironment have not been well understood. The results in this thesis show that systemic oestrogen administration promotes bone angiogenesis and osteogenesis and inhibits adipogenesis. These micro-environmental changes correspond to the changes observed with a physiological oestrogen surge during pregnancy and its depletion during menopause and ageing. Blood vessel physiology during pregnancy, menopause and ageing is regulated by oestrogen signalling via oestrogen receptor alpha (ERα) and G protein-coupled oestrogen receptor 1 (Gper1) but is not dependent on oestrogen receptor beta (ERβ), characterised using endothelial-specific transgenic mouse models. Interestingly, gene expression analysis of young bone endothelial cells (EC) revealed minor sex differences regarding endothelial cell metabolism. Metabolic analyses show increased active mitochondria in adult males compared to females; and demonstrate the role of oestrogen in reducing mitochondrial function. Additionally, glycolytic and mitochondrial stress tests indicate that oestrogen promotes a glycolysis- and oxidative phosphorylation-independent energy metabolism without mitochondrial perturbation. Further characterisation of EC metabolic requirements led to the discovery of fatty acid β-oxidation (FAO) being the primary energy source, more so promoted by oestrogen, drawing FAs from BM adipocyte lipolysis. Oestrogen-deplete conditions such as menopause and ageing lead to the accumulation of ferroptosis-induced lipid peroxides (LPO) due to impaired lipid metabolism when angiogenic type H vessels are lost, with an increase in intracellular ferrous ions. Finally, the novel use of the antioxidant Liproxstatin-1 (Lip-1) closely mimics oestrogenic action in alleviating harmful reactive oxygen species (ROS) and inhibiting LPO generation, by restoring angiogenic type H vessels and stimulating bone formation in aged mice. The findings strongly suggest the use of Lip-1 as a potential therapeutic agent in treating post-menopausal osteoporosis as an alternative to hormone replacement therapy.