Impact of intestinal inflammation on osteoclast differentiation and function
Although the intestinal and skeletal systems are spatially distinct organ systems, they share many overlapping features and are linked by specific cellular and molecular pathways. Works described in this dissertation investigated the impact of intestinal inflammation mediated through immune and infectious etiologies on skeletal homeostasis. Inflammatory bowel disease (IBD) is characterized by severe gastrointestinal inflammation, but many patients experience extra-intestinal disease. Bone loss is one common extra-intestinal manifestation of IBD, which occurs through dysregulated interactions between osteoclasts and osteoblasts. We hypothesized that intestinal inflammation leads to bone loss through increased abundance and altered function of osteoclast progenitors. Using chemical, T cell driven, and infectious models of intestinal inflammation in mice, we observed significant bone loss. Across all models, bone loss was associated with an increase in pro-osteoclastogenic cytokines within bone and an expansion of a specific osteoclast precursor (OCP) population. Intestinal inflammation led to altered OCP expression of the osteoclast co-receptor myeloid DNAX activation protein 12-associating lectin- 1 (MDL-1). OCPs isolated from mice with intestinal inflammation demonstrated enhanced osteoclast differentiation ex vivo compared to controls, which was abrogated by anti-MDL-1 treatment. Importantly, in vivo anti-MDL-1 treatment ameliorated bone loss during intestinal inflammation. Collectively, these data implicate the pathologic expansion and altered function of OCPs and MDL-1 in bone loss during IBD. With an interest in studying the interface of a specific enteric pathogen and bone biology, we investigated how the canonical osteoclastogenic cytokine, receptor activator of nuclear factor kappa-beta (RANKL), impacts monocyte anti- bacterial, inflammatory, and osteoclastogenesis responses to Salmonella enterica subspecies enterica serovar Typhimurium (STm) infection. STm was chosen as model pathogen given that prior work has established a role for intestinal RANKL signaling in the pathogenesis of STm gastrointestinal colonization. RANKL increased the intracellular survival of STm within monocytes while concurrently dampening inflammatory responses to STm infection. Furthermore, STm promoted osteoclastogenesis in RANKL-experienced monocytes. This work concludes with a chapter devoted to addressing future directions and remaining questions to extend these findings.