Regulation of osteoclast differentiation and activation in response to environmental stimuli
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Bone is a biomaterial composed of organic and inorganic molecules that are continuously remodeled to preserve structural integrity and allow adaptation to stress. Two major types of cells are responsible for this process: the osteoblast that synthesizes the bone and the osteoclast that resorbs the bone. A delicate balance between the function of these two cell types is required to maintain proper bone health and body homeostasis. Three independent projects were conducted to investigate the functions of osteoclasts in response to manipulations of their environment. The differentiation and activation of osteoclasts depends largely on cell-cell communication and integration of signals such as stress and metabolic status. The canonical pathway of osteoclast differentiation is driven by receptor activator of NFKB ligand (RANKL), a cytokine produced in large part by cells of the osteoblast lineage. In inflammatory states, RANKL is also made by T cells and synovial cells in the joint. In addition to altering RANKL, inflammation may enhance osteoclast formation through various other cytokines. In project one, we examined the effect of inflammatory cytokine interleukin (IL)-X in a mouse inflammatory arthritis model and found that it is not required for osteoclast activity. Previous studies have reported that other inflammatory cytokines, including as TNF and IL-6 are able to induce osteoclast differentiation in mice, in addition to the RANKL pathway. Project two investigates whether these cytokines could have the same function in humans. In addition to inflammatory cytokines, osteoclasts have been shown to respond to extracellular stimuli such as stress and metabolic status. Factors responsible for integrating these signals, TSC2 and the mTORC1 complex, were investigated for their role in osteoclast activity, regulation of communication between osteoclasts and osteoblasts, and subsequent formation of a high bone mass phenotype. All three projects have clinical correlations in human. Studying the effects of inflammatory cytokines could reveal mechanisms and strategies for prevention of erosions in rheumatoid arthritis and other inflammatory arthritidies. Heterozygous mice for the Tsc2 gene can be used as a mouse model for diseases including tuberous sclerosis complex and Paget’s disease. Moreover, understanding the role of mTORC1 complex activity in regulating bone mass could shed light on the potential effect of long-term rapamycin treatment for patients. As demonstrated through these projects, bone is highly dynamic and regulated by numerous physiological processes.