Application of hydroxycholesterols for alveolar cleft osteoplasty in a rodent model

Background: Bone morphogenetic proteins (BMPs) have played a central role in the regenerative therapies for bone reconstruction including alveolar cleft and craniofacial surgery. However, the high cost and significant adverse effect of BMPs limit their broad application. Hydroxycholesterols (OHCs), naturally occurring products of cholesterol oxidation, are a promising alternative to BMPs. We studied the osteogenic capability of OHCs on human mesenchymal stem cells (hMSCs) and the impact of OHCs on a rodent alveolar cleft model. Methods: HMSCs were treated with control medium or osteogenic medium with or without OHCs. Evaluation of cellular osteogenic activity was performed. A critical-sized alveolar cleft was created and one of the following treatment options randomly assigned to each defect: collagen sponge incorporated with OHCs, BMP-2, or no treatment. Bone regeneration was assessed via radiologic and histologic analyses and local inflammation in the cleft evaluated. Moreover, role of the Hedgehog signaling pathway in OHCs-mediated osteogenesis was examined. Results: All cellular osteogenic activities were significantly increased on hMSCs treated with OHCs relative to others. The alveolar cleft treated with collagen sponge with OHCs and BMP-2 demonstrated robust bone regeneration. OHCs group revealed histologically complete bridging of the alveolar defect with architecturally mature new bone. The inflammatory responses were less in the OHC group compared with BMP-2 group. Induction of OHCs-mediated in vitro osteogenesis and in vivo bone regeneration were attenuated by Hedgehog signaling inhibitor, implicating involvement of the Hedgehog signaling pathway. Conclusions: OHCs may represent a viable alternative to BMP-2 in bone tissue engineering for alveolar cleft. Disclosure: The authors have no commercial associations or financial disclosures that might pose a conflict of interest with any information presented in this article. * These authors contributed equally to this study. ACKNOWLEDGEMENTS: This work was supported by the Annenberg Fund for Craniofacial Surgery and Research at UCLA and UCLA Children's Discovery and Innovation Institute#8232;Today's and Tomorrow's Childrens Fund (TTCF) Bridge Grant. Corresponding author: Reza Jarrahy, MD, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 465 Los Angeles, CA 90095-6960, Email: rjarrahy@mednet.ucla.edu Phone: 310-825-0065 Fax: 310-794-7933 ©2019American Society of Plastic Surgeons

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