Currently, autografts still represent the gold standard treatment for the repair of large bone defects. However, these are associated with donor site morbidity, increased pain, cost and recovery time. The ideal therapy would use biomaterials combined with bone growth factors to induce and instruct bone defect repair without the need to harvest patient tissue. In this line, BMPs have been the most extensively used agents for clinical bone repair, but at supraphysiological doses that are not without risk. Because of the need to eliminate the risks of BMP2 use in vivo, we assessed the ability of three putative osteogenic factors, Nell-1, HMGB1 and CCN2, to enhance the essential processes for bone defect repair in vitro and compared them to BMP2. Although it has been reported that Nell-1, HMGB1 and CCN2 play a role in bone formation, less is known about the contribution of these proteins to the different events involved, such as cell migration, osteogenesis and vasculogenesis. In this study, we investigated the effects of different doses of Nell-1, HMGB, CCN2 and BMP2 on these three processes as a model for the recruitment and differentiation of resident cells in the in vivo bone defect repair situation, using cells of human origin. Our data demonstrated that Nell-1, HMGB1 and CCN2 significantly induced MSC migration (from 1.58 fold increase compared to control), but BMP2 didn't. Interestingly, only BMP2 increased osteogenesis in marrow stromal cells, whereas it inhibited osteogenesis in pre-osteoblasts. Moreover, the four proteins studied promoted significantly endothelial cell migration, reaching a maximum of 2.4 fold increase compared to control, and induced formation of tube-like structures. Nell-1, HMGB1 and CCN2 had these effects at relatively low doses compared to BMP2. This work indicates that Nell-1, HMGB1 and CCN2 might enhance bone defect healing via the recruitment of endogenous cells and induction of vascularization and act via different processes than BMP2.

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Journal Tissue Engineering - Part A
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/607051 - BIO INSPIRED BONE REGENERATION (BIO-INSPIRE)
Fahmy-Garcia, S, van Driel, M, Witte-Bouma, J, van Leeuwen, J.P.T.M, van Osch, G.J.V.M, & Farrell, E. (2017). Nell-1, HMGB1 and CCN2 enhance migration and vasculogenesis, but not osteogenic differentiation compared to BMP2. Tissue Engineering - Part A, 2017(May), 1–24. doi:10.1089/ten.TEA.2016.0537