Tribbles homolog 3 and BMP-2 induced bone formation

University Of California Los Angeles, Los Angeles CA

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Abstract

Project Summary Osteoporosis affects craniofacial skeleton, jeopardizing dental procedures and healing processes. Pathophysiologic processes of aging and osteoporosis are linked to the decreased osteogenic potential of bone marrow mesenchymal stem cells (MSCs) and cell fate shift toward an adipogenic lineage. Although bone morphogenetic protein-2 (BMP-2) is believed to be the most potent osteoinductive factor, efficacy and safety concerns exist, including dose-dependent activation of peroxisome proliferator-activated receptor-γ (PPARγ) and adipogenesis. Moreover, emerging evidence demonstrates aberrant BMP signaling in osteoporotic patients and impaired osteogenic response to BMP stimulation. During the initial funding period, we discovered the reciprocal role of tribbles homolog 3 (Trb3) in the regulation of osteogenic and adipogenic differentiation of MSCs. Importantly, Trb3 enhanced bone regenerative capacity and quality of BMP-2 by inhibiting PPARγ activity and fatty tissue formation. Our preliminary study showed that systemic administration of Trb3 reversed ovariectomy (OVX)-induced osteoporotic phenotype in mice. This renewal aims to further investigate whether Trb3 can promote osteogenesis in a more challenging, systemic bone disease and enhance effectiveness of BMP-2 in the treatment of osteoporotic bone defects. In addition, current systemic therapy is hampered by off-target effects and insufficient efficacy. Thus, this study will further enhance the efficacy and safety of Trb3 delivery by employing our newly developed targeted nanocarriers. The specific hypothesis is that delivery of Trb3 gene via viral vectors or bone targeting exosome mimetics (EMs) will regulate MSC adipo-osteogenic differentiation in osteoporosis, reverse osteoporotic bone loss, and promote bone regeneration efficacy of BMP-2 in osteoporotic bone defects. Three specific aims are proposed to investigate this hypothesis. In Aim 1, we will evaluate the ability of Trb3 to protect against bone loss in OVX or aging rats by injecting viral vector encoding Trb3 into rats. We will also investigate regulatory mechanisms of Trb3 action in preventing osteoporosis using MSCs isolated from OVX or aged rats treated with Trb3. Next in Aim 2, we will evaluate the ability of Trb3 to promote bone healing in OVX rats with peri-implant bone defects. We will also apply BMP-2 in the defects and investigate whether Trb3 treatment can enhance BMP-2 osteogenic effects while reducing defect site adipogenesis. Finally in Aim 3, our recently developed EMs will be applied to deliver Trb3. We will introduce apatite and MSC binding moieties into the EM surface and investigate whether the targeted EMs can be accumulated in bone tissues with low systemic toxicity. Effects of systemic administration of Trb3-loaded EMs on alleviating bone loss will be evaluated in OVX rats. Successful completion of the proposed studies will identify a new strategy that could better regulate adipo-osteogesis of MSCs and bone formation in osteoporosis, and could improve effectiveness of BMPs in the treatment of osteoporotic bone defects.