Bone Marrow Cells Inhibit BMP‐2‐Induced Osteoblast Activity in the Marrow Environment. (23rd October 2018) - Nguyen, Ha Thi
ABSTRACT: Bone morphogenetic protein 2 (BMP‐2) is widely known as a potent growth factor that promotes bone formation. However, an increasing number of studies have demonstrated side effects of BMP‐2 therapy. A deeper understanding of the effect of BMP‐2 on cells other than those involved directly in bone remodeling is of fundamental importance to promote a more effective delivery of BMP‐2 to patients. In this study, we aimed to investigate the effect of BMP‐2 in the marrow environment. First, BMP‐2 adsorbed onto titanium implants was delivered at the tooth extraction socket (marrow‐absent site) or in the mandible marrow of beagle dogs. BMP‐2 could induce marked bone formation around the implant at the tooth extraction socket. Surprisingly, however, no bone formation was observed in the BMP‐2‐coated titanium implants inserted in the mandible marrow. In C57BL/6 mice, BMP‐2 adsorbed in freeze‐dried collagen pellets could induce bone formation in marrow‐absent calvarial bone. However, similar to the canine model, BMP‐2 could not induce bone formation in the femur marrow. Analysis of osteoblast differentiation using Col1a1 (2.3)‐GFP transgenic mice revealed a scarce number of osteoblasts in BMP‐2‐treated femurs, whereas in the control group, osteoblasts were abundant. Ablation of femur marrow recovered the BMP‐2 ability to induce bone formation. In vitro experiments analyzing luciferase activity of C2C12 cells with the BMP‐responsive element and alkaline phosphatase activity of MC3T3‐E1 osteoblasts further revealed that bone marrow cells inhibit the BMP‐2 effect on osteoblasts by direct cell–cell contact. Collectively, these results showed that the effect of BMP‐2 in inducing bone formation is remarkably repressed by marrow cells via direct cell–cell contact with osteoblasts; this opens new perspectives on the clarification of the side‐effects associated with BMP‐2 application. © 2018 American Society for Bone and Mineral Research.