Research Projects

Bone homeostasis is the counterbalance between bone formation and bone resorption. Bone formation is regulated by osteoblasts and achieved through the orchestration of gene expressions throughout the differentiation phase. Osteoclasts are responsible for resorption and bone loss. The two processes in the adult skeleton are balanced, preserving a constant, homeostatically controlled amount of bone. As long as these cells' activities are properly balanced, net bone mass is maintained, and bone homeostasis is preserved. Imbalance in the activities of these cells results in osteoporosis; a skeletal disorder caused by bone loss, usually in postmenopausal women or older men, resulting in low bone mass and deranged skeletal architecture that compromise bone strength leading to fracture. Most of our current therapies for osteoporosis that inhibit bone resorption by osteoclasts also indirectly inhibit bone formation. While these therapies increase bone mass and reduce fracture risk, they do not correct the structural abnormalities that characterize patients with established osteoporosis. Only therapeutic agents that enhance bone formation is capable of doing so. Recent studies highlighting the pivotal role of sclerostin as a negative modulator of osteoblastic activity & bone formation led to the concept that inhibiting sclerostin could be an attractive strategy to treat osteoporosis. Sclerostin, a 213aa protein product of SOST gene is produced by osteocytes and exerts its effect as an inhibitor of bone formation by blocking the Wnt signaling pathway. Sclerostin acts as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. Indeed, a neutralizing antibody against sclerostin, (romosozumab) has been approved by the U.S. FDA in 2019 for the treatment of osteoporosis patients with high fracture risk (REF). However, unbiased studies pertaining to sclerostin biology such as its regulation and interactions with other proteins are limited. Because understanding the mechanism of Sclerostin’s would shed important light on the pathogenesis and treatment of metabolic bone diseases such as osteoporosis, our goal is to evaluate the role of PIM kinase in regulating Sclerostin apparently through phosphorylation. Notably, PIM knock out mice have reduced body size and Runx2 knockout (a master regulator of osteoblast differentiation) mice have decreased PIM1 levels which indicate for a role of PIM in regulating bone turn over by regulating sclerostin is not explored so far. Understanding mechanism of PIM-mediated sclerostin regulation could be therapeutically targeted in the treatment of osteoporosis.