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Plast Reconstr Surg. 2017 Jun;139(6):1385-1396. doi: 10.1097/PRS.0000000000003367.

Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing.

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Los Angeles, Calif.; Baltimore, Md.; Pangyo, Seongnam, Republic of Korea; and Shenyang, People's Republic of China From the Division of Growth and Development and Section of Orthodontics and the Section of Biomaterials, School of Dentistry, University of California, Los Angeles; the Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine; the Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center; and the Department of Pathology and Laboratory Medicine, University of California, Los Angeles; the Department of Pathology, Johns Hopkins University; the Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University; and the Department of Plastic Surgery, First Hospital of China Medical University.



Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model.


A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold.


Results at 4 and 8 weeks showed increased bone formation by micro-computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization.


In summary, the authors' results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.

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