Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Neural epidermal growth factor-like 1 protein (Nell-1) is first studied because of its association with human craniosynostosis. Recently, the osteoinductive ability of Nell-1 is valued, and Nell-1 is used to accelerate the process of fracture healing. However, the role of Nell-1 during the process of osteointegration is unknown. Here we show that activation of Nell-1 in BMSC sheet promotes osseointegration in vivo and in vitro. We found that overexpression of Nell-1 improved osteogenic differentiation and enhanced matrix mineralization (ECM) of BMSCs through increasing expression of Runx2 and Osterix. Activation of Nell-1 up-regulated the expression ratio of OPG/RANKL, which might have a negative influence on osteoclast differentiation. Furthermore, we obtained BMSC sheet-implant complexes transfected with lentivirus overexpressing and interfering Nell-1 in in vivo study, and confirmed that overexpression of Nell-1 promoted new bone formation around the implant and increased the bone-implant contacting area percentage. Our results demonstrate that activation of Nell-1 improves osteointegration by regulating Runx2/Osterix axis and shows the potential of BMSC sheet-implant complexes in gene therapy.