PROJECT SUMMARY/ ABSTRACT The long-term goal of my research program is to develop a comprehensive understanding of how metabolic pathways impact bone health. Consistent with this goal, our vision is to apply strategies to identify novel biological mechanisms, which lead to the development of new treatments that can improve the quality of life for patients with bone fragility. Osteoporosis and osteopenia are late-onset diseases affecting a staggering 54 million people in the U.S addition to the financial burden, osteoporosis-related fractures often lead to multiple comorbidities which significantly reduce longevity. While anabolic agents that increase bone formation, such as parathyroid . In hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects. Therefore, continued development of refined therapeutic options is necessary. Relative to this, the current project aims to harness PTH’s ability to modulate osteoblast bioenergetic capacity to promote bone formation by supplying energy fatty acid substrates to meet this demand. Targeting metabolic pathways in bone cells is a highly provocative tool that can be applied to combat various musculoskeletal conditions which lead to increased fracture incidence (i.e., post-menopausal osteoporosis and age-related osteoporosis). Within this scope, the current project aims to explore the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) via modulation of lipid metabolism on cells within the skeletal niche. Therefore, the overarching hypothesis is that the osteoanabolic actions of iPTH can be enhanced by supplying osteoblasts with exogenous fatty acids. This hypothesis will be tested in two specific aims. The first aim will utilize in vivo model systems to determine whether manipulation in the availability of exogenous fatty acids influences iPTH-induced bone formation. The second aim will further demonstrate that PTH-induced alterations in osteoblast activity rely on increased adenosine triphosphate (ATP) production via fatty acid oxidation using a novel in vitro method. This project is expected to have substantial health-related influence. Specifically, data generated from this project are likely to translate directly to improve clinical outcomes by (1) identifying a novel bone anabolic mechanism, (2) aid in the optimization of dosing strategy and/or efficacy of a current FDA-approved bone anabolic agent to prevent osteoporotic-related fracture, as well as (3) lead to the identification of other pharmaceutical therapies exploiting similar mechanisms, all of which are directly related to improving musculoskeletal health.

Osteoporosis and low bone mass (i.e., osteopenia) are major public health problems affecting a staggering 54 million people in the U.S. New and improved anabolic approaches are needed for the treatment of osteoporosis because current therapies have documented limitations, are cost prohibitory, and some aspects of their mechanism remain in question. This project will identify novel areas of exploration related the intracellular metabolism to improve the efficacy of intermittent parathyroid hormone (PTH)’s ability to stimulate bone formation.