Project Abstract Osteoporosis is a major public health problem in our aging population. New bone anabolic strategies to treat this disease are desperately needed. Parathyroid hormone (PTH) is a central regulator of calcium homeostasis. Through its rapid actions in bone, PTH quickly liberates skeletal stores of calcium and maintains normal blood calcium levels. In addition, PTH also stimulates bone formation, and this property is exploited in the form of once daily injections (teriparatide and abaloparatide) for osteoporosis treatment. Widespread use of PTH therapy is limited by the need for daily injections. In addition, we still do not fully understand why intermittent PTH effectively builds bone while continuous hyperparathyroidism leads to loss of bone mass and some suppression of osteoblast activity. In this research program, we will understand how PTH stimulates bone formation and then use that information to develop next generation orally available bone anabolic therapies. Towards those goals, we recently defined a role for salt inducible kinases (SIKs) as key intracellular mediators of the actions of parathyroid hormone in bone cells. PTH signaling via cyclic AMP and protein kinase A blocks SIK2 and SIK3 activity in cells. Accordingly, genetic and pharmacologic experimental strategies that block SIK2/SIK3 activity effectively mimic the actions of PTH in bone. Here, in Aim 1, we will develop, evaluate, and test ‘next generation’ orally available compounds that block SIK2/SIK3 action and boost bone formation and bone mass in preclinical hypogonadism-associated osteoporosis models. In doing so, we will merge genetic and pharmacologic approaches to ensure that these compounds indeed act via their intended targets (SIK2 and SIK3) to stimulate bone formation. Having demonstrated therapeutic efficacy of novel small molecule SIK2/SIK3 inhibitors, next we will define their mechanism of action in bone cells in Aim 2. Unbiased phospho-proteomic profiling revealed potential control of phosphoinositide 3-kinase and AKT signaling by the PTH/SIK pathway. This observation may explain why continuous hyperparathyroidism fails to fully stimulate bone formation by osteoblasts. Here we will study how PTH/SIK signaling intersects with the AKT pathway in bone cells at the level of cellular energetics, and then use this information to test the model that reduced AKT activity helps explain bone loss due to continuous hyperparathyroidism. Taken together, these inter-related Aims will elucidate novel signal transduction models in bone cells and define the mechanism of action of a new, orally-available osteoporosis bone anabolic therapy.