Bone formation is regulated by systemic hormones and local growth factors which influence bone cell replication and differentiation. The bone morphogenetic proteins (BMP) are osteoinductive proteins which were originally identified by their presence in extracts of demineralized bone. At least six related members of this family have been identified by molecular cloning and are called BMP-2 through BMP-7. These molecules are part of the TGFbeta superfamily based on primary amino acid sequence homology (Rosen and Thies, 1992). The BMPs possess osteoinductive properties and are capable of inducing the formation of new cartilage and bone when implanted ectopically in a rodent assay system or when used with in vivo fracture healing models. It is hypothesized that osteoblasts develop from a multi-potential stromal stem cell in the bone marrow. The objective of this research proposal is to determine if the introduction of the gene for BMP (i.e. BMP-2) into bone marrow stromal cells will 1) transform the stromal cells into osteoprogenitor cells, 2) demonstrate the presence of an autocrine loop for BMP by activation of an endogenous BMP gene. The initial experiments in this proposed study would examine the influence of BMP on the growth and differentiation of stromal and fibroplastin, cells in an vitro culture system. Various continuous stromal cell lines and fibroblast lines will be tested. These cell lines will be infected by a BMP-2 containing retroviral vector. If the culture studies are successful it would then be appropriate to test these concepts in an in vivo rodent fracture model. These differentiated stromal and fibroplastin cell lines which can provide sustained local production of BMP at the fracture site will be employed to heal a bone defect. This research will increase our understanding of the relationship between the TGF-beta superfamily and bone growth and development and fracture repair.
|Lieberman, J R; Daluiski, A; Stevenson, S et al. (1999) The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J Bone Joint Surg Am 81:905-17|
|Lieberman, J R; Le, L Q; Wu, L et al. (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 16:330-9|