Metabolic bone diseases characterized by low bone mass are highly prevalent. Many factors contribute to the development of these diseases, including poor nutrition, gut microbiota, and inflammation. Inflammatory effectors can tip the balance between bone formation and resorption to favor osteoclastic bone resorption. As bone mass declines, the risk of experiencing a fracture increases. While most fractures heal naturally, excessive inflammation can disrupt the wellorchestrated series of cellular and molecular events that would normally heal the broken bone. However, the contributors to this excessive inflammatory response to bone fractures remains poorly understood. The overarching goal of this dissertation is to investigate the inflammatory and nutritional contributors to bone homeostasis and repair.

Using highly informative pre-clinical murine models we sought to address the following three aims:​ 1) establish the role of the inflammatory modulator Wnt5a in osteoblast and osteoclast coupling;​ 2) examine the influence of aging on the inflammatory response to fracture;​ and 3) determine whether probiotics regulate inflammation during fracture healing. In Aim 1 and 2, murine genetic models to conditionally delete Wnt5a in osteoclasts and IL-17ra in periosteal mesenchymal cells were employed. In Aims 2 and 3, the murine mid-diaphyseal femoral fracture model was used to assess fracture healing.

The findings from this dissertation identify inflammatory effectors as important components of bone homeostasis and repair. Aim 1 redefined the role of Wnt5a in controlling bone homeostasis by identifying a unique phosphorylated Wnt5a that is secreted by mature osteoclasts to control bone formation. Results from Aim 2 revealed that increased aged results in a unique systemic cytokine profile after fracture that includes higher levels of the anti-osteogenic proinflammatory cytokine IL-17a. Lastly, Aim 3 demonstrates that influencing the gut microbiome through supplementation with the probiotic species B. adolescentis can dampen systemic inflammation to accelerate healing and protect the intact skeleton against bone loss. The collective results of this dissertation bring novel insight to the growing body of literature which indicate that inflammation is a key negative contributor to bone maintenance and repair. Additionally, we identify probiotic supplements as a therapeutic approach to dampen the negative consequence of systemic inflammation after traumatic bone injuries.