Induced regeneration of calvaria by bone morphogenetic protein (BMP) in dogs

In the adult dog, a 14-mm skull trephine defect regenerates only incompletely in the lifetime of the individual. Only about half of the defect is repaired; the regenerated part develops by extension of growth from the bony rim. Correlated roentgenographic and histomorphometric methods demonstrate that new bone develops by proliferation of preexisting osteoprogenitor cells lining the diploë and perivascular cells of the bone marrow stroma. An autogeneic bone graft, including bone marrow, provides a supplementary supply of cells in a homostructural framework and generally completes the repair process. Transplants of bone marrow alone fail to repair the defect. Implants of bovine bone morphogenetic protein (bBMP) and a carrier consisting of matrix gamma-carboxyglutamic acid rich protein (without any additional bone or bone marrow) induce repair almost as completely as an autograft. BMP-induced bone regeneration is incomplete in the thin lateral temporal marrow-deficient part of the cranium. Implants of BMP plus bone marrow induce complete repair, suggesting that calvarial bone regeneration is bone marrow stroma-dependent for a supply of target cells. The target for BMP in cranial bone regeneration is the perivascular connective tissue cells (pericyte) of the host bed marrow stroma and endosteum. The molecular mechanism of differentiation of pericytes into osteoprogenitor cells is not known, but the process is irreversible, heritable, and presents a solvable problem.