Unraveling Mechanisms Driving Female-Specific Osteogenesis after Disrupting a Brain-to-Bone Circuit

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ABSTRACT Estrogen is a critical regulator of energy balance and skeletal metabolism. Women spend more than 1/3 of their lives in an estrogen depleted state; drastically increasing their risk for age-related bone diseases such as osteoporosis and fractures. Recent work by our lab and others demonstrates that loss of central estrogen signaling in the arcuate nucleus (ARC) of the hypothalamus results in a female-specific elevation in bone mass and strength, however molecular mechanisms that govern those responses are still unknown. I hypothesize that deletion of ERa in the ARC of Esr1Nkx2-1Cre and ERaKOARC female mice releases a humoral brain-dependent osteogenic factor (BDOF) which inherently changes resident SSCs, fating these cells for osteogenesis, and that the changed SSCs are sufficient to enhance fracture repair and reverse bone loss in osteoporotic and aged mouse models. For this project I will 1) use an unstabilized tibia fracture model to ask if Esr1Nkx2-1Cre females have enhanced fracture repair. 2) I will use my new bioassay to test HPLC/FPLC fractionated mouse plasma to identify and purify the BDOF, and 3) I will identify the molecular signals driving osteoblast expansion in female mutants using a mutant-derived SSC transplant model. Answering these questions is critical for the advancement of therapeutics for bone-related diseases in women and men.