Grant: CIHR Fellowship

Osteoporosis (OP) is the most common bone disease worldwide, causing bones to become weak and more likely to fracture. This condition is caused by an imbalance between building new bone and breaking down old bone, controlled by specialized cells known as osteoblasts, which create bone tissue, and osteoclasts, which break it down. As life expectancy increases globally, the implications of this disease are significant. Therefore, demand is increasing for effective therapies that can promote bone formation. Bone building medications, like parathyroid hormone (PTH) analogues and anti-sclerostin antibody (Scl-Ab), help build bone and prevent fractures. However, the effectiveness of these medications, especially Scl-Ab, diminishes over time. Critically, major knowledge gaps exist in our understanding of why the bone building activity of these medications decline. Osteoblast precursors, which mature into osteoblasts, may be crucial in this process. The bone building effects of PTH and Scl-Ab involves increasing osteoblast precursor numbers and promoting their maturation into osteoblasts. Prolonged use of Scl-Ab is associated with reduced precursor numbers with impaired cell division. Based on these findings, I speculate that the reduced effectiveness of osteoporosis bone building medications over time is due to maturation of precursors into osteoblasts with insufficient replacement of these cells to maintain their numbers. This study will use cutting edge technologies to track the fate of osteoblast precursors and define their genetic profiles following Scl-Ab treatment in a mouse osteoporosis model. This will help us understand how these medications cause osteoblast precursors to mature and divide, and which genes in these cells may be causing these medications to become less effective. Ultimately, this work will discover new gene targets to extend the efficacy of current therapies, and exploit this knowledge to develop superior treatment strategies for patients with OP.