Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. For example, the immune system comprises cells that are spawned in the bone marrow reservoir, which contains niches that contribute to lymphocyte development. Moreover, various factors produced during immune responses are capable of regulating the structure of bone. Overlap also occurs during development;cells that regulate bone turnover share a common precursor with inflammatory immune cells. These cells may be anatomically restricted, in part, due to an intrinsic signaling network that is analogous to many of the lymphocyte costimulatory signals. Although mechanisms have evolved to prevent the immune system from excessively interfering with bone homeostasis, pathologic bone loss is a common sequela associated with various inflammatory diseases. Efforts are currently underway to further characterize how these two organ systems overlap, and to develop therapeutic strategies that benefit from this understanding. This application stems, in part, from our long-standing desire to elucidate how osteoclasts are regulated during inflammatory assaults by molecules operating in the RANKL signaling axis. Our preliminary data have shown that certain inflammatory signals can antagonize the effects of RANKL on osteoclast differentiation. We have shown that Toll-like receptor (TLR) stimulation of bone marrow precursors strongly inhibits RANKL-induced osteoclast differentiation ex vivo. This inhibitory effect of TLR stimulation, which is mediated by the production of type 1 interferons, is somewhat surprising because TLR stimulation promotes inflammation-induced bone loss in vivo. Therefore, our preliminary data-in conjunction with previous studies by our and other groups showing that activated T cells play pivotal roles in inflammation-induced bone loss-raise fundamental questions about the cell types that produce the RANKL necessary to induce osteoclast differentiation, and how this differentiation is regulated by other inflammatory cytokines during inflammation-induced bone loss. We propose to tackle these questions by pursuing the following specific aims: (1) determining the primary cell types that produce the enhanced levels of RANKL required for excessive osteoclast formation in vivo during inflammation-induced bone loss;(2) determining how RANKL induces osteoclastogenesis in the presence of antiosteoclastogenic factors that are present in the local microenvironment when TLR-stimulating bacterial products induce inflammation;and (3) determining the roles of osteoblast-lineage cells that are stimulated by bacterial products or lymphocyte-derived inflammatory cytokines in inflammation-induced bone loss. These studies will provide insights into how different molecules cooperate to induce osteoclast differentiation, which in turn, may help improve the treatment and prevention of bone destruction associated with various inflammatory diseases, such as periodontitis. Osteoclasts are the principal, if not the only, cells that can resorb bone. Thus, understanding the molecular pathways leading to the differentiation and activation of osteoclasts will help improve the treatment and prevention of bone destruction associated with various inflammatory diseases such as periodontitis.
