Mechanisms of osteoinduction/chondroinduction by demineralized bone.

Demineralized bone is widely used for osseous reconstructive procedures. Bone morphogenetic proteins (BMPs) have been studied as the putative active components of demineralized bone; recombinant BMPs are Food and Drug Administration-approved for use with scaffold carriers. An experimental three-dimensional in vitro model was developed to allow comparison of early changes in signaling and gene expression in cells exposed to demineralized bone particles (DBPs) or to BMP and/or transforming growth factor beta (TGF-beta). The culture device consists of a bilayer of porous collagen lattice that contains either a packet of DBPs or an insert of the dense collagen scaffold with BMP and/or TGF-beta. As expected, BMP and TGF-beta induced distinct signaling pathways and events in human dermal fibroblasts; DBPs signaled both pathways and their target genes. A mixture of BMP and TGF-beta stimulated the production of extracellular matrix chondroitin that approximated the composition that was stimulated by DBPs, but to a lesser amount. Although BMP was originally isolated as the active factor in DBPs, it does not show DBPs' effects on signaling and chondroinduction in vitro. Multiple members of the TGF-beta superfamily and other constituent factors may be involved in skeletal induction of human dermal fibroblasts by DBPs. This in vitro culture system may be useful to provide a rational basis for designing improved osteoinductive/chondroinductive materials.