Rejuvenating Skeletal Health Through A Novel Brain-Bone Axis

Project Summary/Abstract Interorgan communication between the brain and peripheral tissues maintains a range of homeostatic responses. Efforts to identify new facets of interorgan crosstalk remain sparse. Missed opportunities exist because of the siloed nature of physiological research, especially between the brain and body. Cracking the molecular code in the brain-body dialog is also technically challenging and requires time-consuming, interdisciplinary preclinical in vivo studies. We previously discovered that eliminating ERa in a subset of hypothalamic neurons leads to a massive increase in trabecular bone mass and strength that persists with aging in female mice. Our focus on a brain-bone interaction that influences bone mass and bone fat underscores the potential role of select neurons to significantly alter peripheral tissues. Here, we will ask how this brain- derived factor increases bone mass while permanently decreasing bone fat, two opposing features of skeletal aging. In new data, we find that the high bone mass in our mutant mouse model system results from humoral rather than neuronal cues. An essential first step toward translating this work will be to identify this circulatory anabolic bone factor. While this goal is simple in principle, it is extremely difficult to achieve. We were fortunate to discover that this high bone mass phenotype reverses with a dietary challenge. High-resolution genomic approaches then allowed us to identify and test the most promising candidates through gain-of-function and loss-of-function approaches. Using in vitro, ex-vivo, and in vivo model systems, we provide the first molecular and cellular insights into how the brain influences bone mass, bone fat, and skeletal stem cell function. We will elucidate how and why this brain-derived anabolic bone factor increases bone formation. Our team brings together expertise in neuroendocrinology, bone and skeletal stem cell biology, and the clinical practice of treating metabolic and bone disorders. We are using state-of-the-art methods to pursue hypothesis- driven questions aimed at decoding a powerful dialog between the brain and bone. Eventually, we wish to translate these preclinical studies to skeletal and metabolic disorders that are associated with or accelerated in human aging. Our research program fits squarely within this new NIA mandate to transform our understanding of interorgan interactions and advance strategies for improving age-related decline in skeletal health, especially in women.