Plastic Surgery Research Council
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Presenter: Reza Jarrahy, MD
Co-Authors: Li A; Hokugo A; Sorice S; Buck A; Zuk P

Background: Bone morphogenetic proteins (BMPs) have played a central role in the development of regenerative therapies for bone reconstruction. However, the high cost and side effect profile of BMPs limits their broad application. Oxysterols are a promising alternative to BMPs. We studied the impact of Oxy49, a novel oxysterol analogue, on the in vitro and in vivo osteogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and the mechanisms by which it mediates its effects.

Materials and Methods: Rabbit BMSCs were isolated from iliac crests, cultured, and treated with control media or varying concentrations of oxysterol and/or BMP-2. Osteogenic differentiation was assessed via alkaline phosphatase (ALP) assay, quantitative RT-PCR of osteogenic genes, and mineralization assays (Von Kossa staining). BMSCs were also treated with cyclopamine, a Hedgehog (Hh) signaling pathway inhibitor. Critical-sized rabbit calvarial defects (6mm) were treated with either 1) collagen sponge with 10 mg Oxy49, 2) collagen sponge with 1 mg Oxy49, 3) collagen sponge incorporating inert vehicle (control), or 4) no treatment. The calvarium was harvested after seven weeks for histologic and radiographic analysis with micro-computed tomography.

Results: Rabbit BMSCs treated with Oxy49 demonstrated increased ALP activity, up-regulation of osteogenic gene expression, and increased mineralization of cultures. These effects were mitigated by cyclopamine, implicating the Hh signaling pathway in Oxy49-mediated osteogenesis. Rabbit BMSCs treated with Oxy49 demonstrated osteogenic differentiation with an efficacy similar to that of cells treated with BMP-2. Critical-sized rabbit calvarial defects showed bone regeneration when treated with Collagen sponges combined with Oxy49.

Conclusions: Oxy49 induces osteogenic differentiation in rabbit BMSCs as effectively as BMP-2 in both in-vitro and in-vivo studies. This activity is in part mediated by the Hh signaling pathway. Oxysterols may therefore represent a viable alternative to BMP-2 in bone tissue engineering. Further investigation of this potent growth factor are currently underway.

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