Project Summary/Abstract: Glucocorticoids (GC) are multisystem essential hormones, highlighted by the fact that nearly every tissue in the body expresses glucocorticoid receptors (GR). Although released from the adrenal glands in a hormonal fashion, GC levels are regulated at the tissue level in a paracrine manner by conversion enzymes such as Hsd11b1 and Hsd11b2. While the detrimental effects of exogenous pharmacological doses of GC are well known, the roles for endogenous, adrenal-derived, physiological concentrations of GC are poorly understood, particularly in musculoskeletal aging. Endogenous GC are known to be dysregulated in aging: in older humans and mice, circulating GC levels increase, lose proper circadian cycling, and show amplified local conversion to active forms via expression of enzymes like Hsd11b1 with age in bone. Given the adverse effects of exogenous GC on the skeleton, we originally predicted that deletion of the GR would protect the skeleton from aging-induced bone loss. However, the opposite was surprisingly true: conditional loss of GR in Osx-expressing cells promoted low bone mass, osteoblast dysfunction, and increased bone marrow adipose tissue (BMAT) in young adult mice that worsened in old mice. As a possible explanation for this finding, GC also bind to the mineralocorticoid receptor (MR), and do so with higher affinity than to GR. Our preliminary data support a paradigm shift where accelerated skeletal aging could be occurring through aberrant MR expression or via failure of GC bio-protective mechanisms (e.g., excessive Hsd11b1 GC activation without counterbalance from Hsd11b2 activity). Our published studies also show that conditional loss of GR in Osx-expressing cells causes systemic changes suggestive of bone-mediated interorgan communication (IOC) in aged mice including low muscle mass, low physical activity, and increased fat despite no loss of GR tissues outside of bone. Our preliminary data suggest that GC-activated MR is a novel but untested mediator of bone-initiated IOC in aging evident in this model. We have developed inducible Osx-targeted MR conditional knockout and MR overexpressing mouse models, and an inducible Osx-targeted conditional knockout mouse model of Hsd11b1. We will leverage these novel animal models to test the contribution of local GC activation and signaling through the MR within the skeletal niche to mechanisms of bone aging and IOC. Our goal is to determine the molecular mechanisms and causal role of adrenal-derived endogenous GC in the development of an aging phenotype in bone, BMAT, and IOC with peripheral tissues like skeletal muscle and fat. We propose that disrupted IOC from abnormal bone MR expression or activation results in accelerated tissue aging. MR inhibitors such as eplerenone are used clinically for the regulation of blood pressure, presenting a unique opportunity for drug repurposing to improve musculoskeletal function with age and thus address a major clinical problem. Successful completion of this research will significantly advance understanding of fundamental pathways in the biology of musculoskeletal aging and will identify new therapeutic targets for preventing frailty with age.

This project will test the hypothesis that interorgan communication between the adrenal glands and skeleton via endogenous glucocorticoids is a key component of aging-related musculoskeletal dysfunction, and will test whether signaling downstream of endogenous glucocorticoids is mediated by the mineralocorticoid receptor or glucocorticoid receptor in aging bone.