| Osteoporosis is a serious problem leading to fractures, decreased quality of life, and permanent disability. As the population ages, a better understanding of the disease is essential as all current therapies to treat osteoporosis suffer from significant limitations. The current standard of care for osteoporosis is bisphosphonate therapy which reduces bone turnover and can weaken bone over time, in addition to rare side effects such as jaw necrosis and atypical fractures. Recombinant parathyroid hormone (PTH) carries a black box warning regarding carcinogenic potential and thus can only be used for short term benefits. Calcium supplementation can increase the risk of cardiac events. As a result of these serious limitations with current osteoporosis therapeutics, there is significant disagreement in the field regarding which patients should be treated. Despite attempts to predict fracture risk, uncertainty remains regarding which patients would benefit from therapy. This uncertainty necessitates a better understanding of osteoporosis and options for therapeutic paths.;The purpose of this project is to advance understanding of how osteoblasts and osteoclasts interact in osteoporosis by establishing an in vitro human bone remodeling model to understand new facets of the disease and to explore the effects of different therapeutic treatments. First, we developed an in vitro co-culture bone remodeling model using human mesenchymal stem cells differentiated to osteoblasts and THP-1 human acute monocytic leukemia cells differentiated to osteoclasts. Next, we altered osteoblast and osteoclast behavior in the model by lentiviral transduction of osteoblasts to express tethered ligands. We then incorporated bisphosphonates, the current standard of care for osteoporosis, into the model. Finally, we induced an inflammatory osteoporosis phenotype in the model using inflammatory cytokines. Future directions for the project include transitioning the model to 3D and using the model to study other bone diseases such as osteopetrosis and Paget's disease. |
