Grant: Operating Grant

Musculoskeletal disorders affect people of all ages, severely compromising their health and well-being. The destruction of bone is characteristic of several classes of diseases, including rheumatoid arthritis, osteoporosis, and periodontitis. Osteoclasts are the cells responsible for resorbing bone in healthy tissue (to mainain good bone quality) and abnormally in these disorders. The molecular factor RANKL has been identified as a critical stimulator for osteoclast formation and function, and was shown to play an important role in mediating bone destruction in inflammatory arthritis, periodontitis, and cancer metastasis to bone. However, we have recently found that although RANKL is necessary during initial stage of osteoclast formation, in the later stages, proliferating bone marrow cells produce factors that can substitute for RANKL and induce successful osteoclast formation. The proposed studies will address the role of co-stimulatory receptors and their potential ligand identified during previous cycle of funding, in mediating osteoclast activation by proliferating cells in pathological situation of bone metastasis from breast cancer and physiological situation of recovery from bleeding. The results of these studies may lead to the development of novel targeted therapeutic interventions for inflammatory arthritis, metastatic bone disease and hematolytic anemias.