The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging

Abstract

Hallmarks of aging‐associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging‐associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR‐CKO; GRfl/fl:Osx‐Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3‐ and 6‐month‐old) mice. GR deficiency in Osx‐expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR‐CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole‐body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR‐CKO osteoblastic cultures in a glucocorticoid‐dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR‐deficient bone on whole‐body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).

Bone marrow adiposity modulation after long duration spaceflight in astronauts

“…Contrary to estrogens, the steroid hormone cortisol can upregulate BMA. Cortisol and glucocorticoid receptor knock-out have been associated with higher BMA 58 . In our cohort, morning cortisol levels increased in both sexes during spaceflight and rapidly returned to baseline postflight (Fig.…”

Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat

“…In addition to the unexpected finding of a fat phenotype driven by Osx-Cre , we also did not anticipate the strong effect of age on activation of this Cre . Previous studies utilizing this Cre driver primarily utilize mice under 6 months of age, and the few studies with mice at or beyond 1 year of age did not describe, or specifically look for, Cre expression outside of bone 39 – 41 . Since this study was undertaken to examine the role of IKKα in bone, studies of fat and metabolism were not initially planned.…”

Metabolic regulation by biomaterials in osteoblast

“…Several studies have shown that Osterix can promote mitochondrial biogenesis and function in osteoblasts ( Shahi et al, 2017 ). It does so by activating the expression of genes involved in oxidative phosphorylation and mitochondrial respiration, which results in increased ATP production and enhanced cellular metabolism ( Pierce et al, 2022 ). Osterix also regulates the expression of genes involved in glucose metabolism, including GLUT1, a glucose transporter that facilitates glucose uptake and utilization in osteoblasts ( Kong et al, 2021 ).…”