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Application of Hydroxycholesterols for Alveolar Cleft Osteoplasty in a Rodent Model

Bakshi, Reena M.D.; Hokugo, Akishige D.D.S., Ph.D.; Zhou, Situo M.D.; Zhang, Zheyu B.S.; Wang, Lixin D.M.D.; Rezzadeh, Kameron M.D.; Segovia, Luis Andres M.D.; Jarrahy, Reza M.D.

Plastic and Reconstructive Surgery: May 2019 - Volume 143 - Issue 5 - p 1385-1395
doi: 10.1097/PRS.0000000000005528

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, naturally occurring products of cholesterol oxidation, are a promising alternative to BMPs. The authors studied the osteogenic capability of hydroxycholesterols on human mesenchymal stem cells and the impact of hydroxycholesterols on a rodent alveolar cleft model.

Methods: Human mesenchymal stem cells were treated with control medium or osteogenic medium with or without hydroxycholesterols. Evaluation of cellular osteogenic activity was performed. A critical-size alveolar cleft was created and one of the following treatment options was assigned randomly to each defect: collagen sponge incorporated with hydroxycholesterols, BMP-2, or no treatment. Bone regeneration was assessed by means of radiologic and histologic analyses and local inflammation in the cleft evaluated. Moreover, the role of the hedgehog signaling pathway in hydroxycholesterol-mediated osteogenesis was examined.

Results: All cellular osteogenic activities were significantly increased on human mesenchymal stem cells treated with hydroxycholesterols relative to others. The alveolar cleft treated with collagen sponge with hydroxycholesterols and BMP-2 demonstrated robust bone regeneration. The hydroxycholesterol group revealed histologically complete bridging of the alveolar defect with architecturally mature new bone. The inflammatory responses were less in the hydroxycholesterol group compared with the BMP-2 group. Induction of hydroxycholesterol-mediated in vitro osteogenesis and in vivo bone regeneration were attenuated by hedgehog signaling inhibitor, implicating involvement of the hedgehog signaling pathway.

Conclusion: Hydroxycholesterols may represent a viable alternative to BMP-2 in bone tissue engineering for alveolar cleft.

Los Angeles, Calif.

From the Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles.

Received for publication February 6, 2018; accepted September 14, 2018.

The first two authors contributed equally to this study.

Disclosure:The authors have no commercial associations or financial disclosures that might pose a conflict of interest with any information presented in this article.

Reza Jarrahy, M.D., Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 465, Los Angeles, Calif. 90095-6960,

Copyright © 2019 by the American Society of Plastic Surgeons