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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, and periodontitis. Additionally, osteoblast differentiation capacity of skeletal stem cells must be tightly controlled, as inadequate bone formation results in low bone mass, skeletal fragility, and bone healing defect, while over-exuberant osteogenesis results in extra-bone formation in the soft connective tissues, such as trauma-induced heterotopic ossification and fibrodysplasia ossificans progressiva by a genetic mutation.

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, differentiation, and activation under pathological conditions. 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 technologies. In these technologies, nanoparticles, liposomes, exosomes, or adeno-associated virus (AAV) are modified to home to the bone surface and deliver RNA interference and/or healthy gene 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 via systemic infusion or local implantation could be used as a therapeutic approach for patients suffering with low bone density disorders, such as osteoporosis, bone fracture healing defect, or critical-sized bone defect. Furthermore, these technologies can be used to directly correct a genetic mutation in the body in order to treat and/or cure skeletal rare diseases with monogenic mutations, such as fibrodysplasia ossificans progressiva or osteogenesis imperfecta.

 

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