Bone morphogenetic proteins 2 through 8 have the ability to induce the in vivo transformation of extraskeletal mesenchymal tissue into bone. The aims of this investigation were to determine the optimal responding tissue and the specificity of the inductive effect of bone morphogenetic protein 3. The optimal responding tissue was found to be skeletal muscle. The specificity of this response to bone morphogenetic protein 3 was compared with that of recombinant human basic fibroblast growth factor, recombinant platelet-derived growth factor, and recombinant insulin-like growth factor. Bone morphogenetic protein 3 was the only factor that induced de novo bone formation.
This ability to transform muscle into bone was tested in 7 × 7 mm irradiated skull defects in the rat. After 1500 rads of exposure, these defects showed no significant signs of healing by 8 months. When these defects were treated with the microvascular transfer of a nonirradiated muscle flap, they had 8 percent healing at 4 months and 37 percent healing by 8 months. Defects treated with 30 μg bone morphogenetic protein 3 (without the muscle flap) achieved 50 percent healing by 4 months and 64 percent healing by 8 months. When the defects were treated with both the muscle flap and bone morphogenetic protein 3, there was 96 percent healing by 4 months and 100 percent healing by 8 months (p < 0.015, compared with bone morphogenetic protein 3 alone at both time points). At 8 months, the transplanted muscle was entirely transformed into bone and healed the skull defect with newly generated bone indistinguishable from the surrounding calvarial tissue. These findings suggest a potential clinical utility of bone morphogenetic protein 3-induced bone formation in skeletal reconstructions. Furthermore, they also show that there is a collaborative requirement for both the osteoinductive factor bone morphogenetic protein 3 and the presence of competent responsive cells in the wellperfused muscle.
St. Louis, Mo., and Baltimore, Md.
From the Division of Plastic Surgery and the Mallinckrodt Institute of Radiology at the Washington University School of Medicine and the Department of Orthopedic Surgery at The Johns Hopkins School of Medicine. Received for publication September 20, 1994; revised June 30, 1995.
Presented in part at the 78th Annual Surgical Forum of the American College of Surgeons, in New Orleans, Louisiana, on October 12, 1992.
Roger K. Khouri, M.D.
Division of Plastic Surgery Washington University School of Medicine One Barnes Hospital Plaza, Suite 17424 St. Louis, Mo. 63110