Friday, November 22, 2024
11/22/2024
Summary The use of autogenous bone graft is the most common clinical approach for bone regeneration. Although, the practice has resulted in high rates of fusion success, there are challenges with increased operative time, limited availability of autologous bone, blood loss and donor-site morbidity. Thus, there is a significant attention on therapeutic agents that can promote bone regeneration, as suitable alternatives to autogenous grafts. Meanwhile, the effectiveness of many of the current osteogenic therapeutic approaches is plagued by safety concerns. We propose an innovative treatment strategy for bone regeneration that is based on Gpnmb, discovered by our group. We identified Gpnmb (osteoactivin, OA) as a novel bone anabolic agent that also acts as a positive regulator of osteoblast (OB)-mediated bone formation. The Gpnmb cDNA encodes transmembrane proteins (~574 amino acids) that are heavily glycosylated with several functional domains. We found that the recombinant Gpnmb protein (rGpnmb, containing 472 amino acids) derived from the extracellular portion of Gpnmb possesses remarkable osteoinductive and osteogenic properties. A new peptide (Gpnmb-p containing 18 amino acids; 2kDa) derived from the intracellular portion of Gpnmb showed comparable efficacy with rGpnmb. We observed that without a suitable delivery system, upon injection, Gpnmb-p diffuses way from injection site. The thermoresponsive hydrogel platform will ensure that Gpnmb-therapeutics can reach fusion site (in liquid form) while maintaining the effective dose at bone regenerative site through sol-gel transition that occurs at physiological temperature. The overarching hypothesis of our project is that delivery of Gpnmb-therapeutics using thermoresponsive hydrogels at the bone fusion site will promote osteogenic differentiation and function as well as angiogenic response while minimizing off-target distribution leading to improved efficacy and safety. The project will proceed via three specific aims: (1) To fabricate and characterize thermoresponsive Gpnmb-hydrogels. In this aim, we will prepare and characterize thermoresponsive Gpnmb- hydrogels using triblock PLA-b-PEG-b-PLA copolymer platform. (2) To assess the mechanistic basis by which Gpnmb-hydrogels promote OB differentiation/function and angiogenesis. We expect to reveal and compare key molecular targets that are associated with Gpnmb-p as a soluble osteogenic factor versus when it is applied as a matricellular in enhancing OB differentiation/function and angiogenic response. (3) To evaluate efficacy and safety of Gpnmb-hydrogels in bone regeneration. In this aim, we will apply the spinal fusion model in rats (osteoporotic and non-osteoporotic) to evaluate in-vivo efficacy of Gpnmb-p-hydrogels. The project will provide valuable evaluation of Gpnmb-hydrogels as a novel therapeutic strategy for bone regeneration with the potential to serve as an alternative to autogenous bone graft. Mechanistic assessment of new and innovative therapeutic targets of Gpnmb-p could have a broad therapeutic applicability.
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