Combining Smoothened Agonist (SAG) and NEL-like protein-1 (NELL-1) Enhances Bone Healing.

Background: Non-healing 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, we examined the additive / synergistic effects of Hedgehog (Hh) and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. Here, we sought to leverage our previous findings by applying the combination of Smoothened agonist (SAG), Hh signal activator, and NELL-1 to an in vivo critical size bone defect model. Methods: 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) or SAG + NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disc with hydroxyapatite coating was used as an osteoinductive scaffold. Results: Results at 4 and 8 weeks showed increased bone formation by micro-computed tomography analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG + NELL-1). This included greater bone healing scores, increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG + NELL-1, accompanied by increased defect vascularization. Conclusions: In summary, our results suggest that combining the Hh signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-sized bone defects. Future directions will include optimization of dosage and delivery strategy for a SAG + NELL-1 combination product. (C)2017American Society of Plastic Surgeons

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