Bone mass reflects the coupled balance of activity of osteoblasts to synthesize and osteoclasts to degrade bone matrix. Coupling of the activity between these two lineages is required for balance in bone remodeling, and dysregulation of this process is a major mechanism in the pathogenesis of many of human skeletal disorders, such as osteoporosis, inflammation-induced bone loss, Paget's disease of bone, and heterotopic ossification.
Osteoporosis affects approximately ten million people in the US over the age of 50, with around 1.5 million suffering from osteoporosis-related fractures each year. Unfortunately, the prognosis for patients who suffer these kinds of fractures can be poor; approximately 20% of patients with osteoporosis who suffer a hip fracture will die within a year. Similarly, patients with inflammatory arthritis develop focal articular erosions and systemic bone loss, resulting in osteopenia/osteoporosis. New approaches are needed to address the bone manifestations of inflammatory arthritis for approximately 1.3 million Americans with rheumatoid arthritis because disease modifying agents are inadequate to fully prevent systemic bone loss. Whilst there are some therapeutic options already available, it is crucial that further novel therapeutic strategies are developed. Some existing options focus on inhibiting bone resorption, however many are associated with a variety of undesirable side effects. For example, some therapies that increase bone formation, such as teriparatide, also increase bone resorption and a risk in bone tumor, and treatments that block bone resorption, such as bisphosphonates, arrest new bone formation along with atypical fractures and osteonecrosis of the jaw.
Understanding the molecular mechanisms that regulate these activities is a key to developing improved therapeutics to treat human skeletal disorders. To this end, we took advantage of an unbiased high-throughput screens to identify new proteins that control osteoblast and osteoclast commitment and activation in skeletal biology. Alternatively, using the premise that tissues emerging from similar points during vertebrate evolution may share common intracellular signaling networks to guide their activity, we have sought to leverage our extensive knowledge obtained from the immune system to understand the mechanism in which bone cells are regulated.
For the above proteins that we identified, we have developed sophisticated in vivo gene transfer systems. In these systems, nanoparticles or adeno-associated virus are modified to home to the bone surface and deliver RNA interference to osteoblasts and osteoclasts, thus affecting their activity. The impact of this work could have far reaching effects. If the molecular pathways regulating osteoclast/osteoblast coupling can be better understood, then targeted approaches to promote osteoblast activity could be used as a therapeutic approach for patients suffering with low bone density disorders.