INFLUENCE OF OSTEOGENIC PROTEIN-1 (OP-1-BMP-7) AND TRANSFORMING GROWTH-FACTOR-BETA-1 ON BONE-FORMATION IN-VITRO

The bone morphogenetic proteins (BMPs) and transforming growth factor- beta s (TGF-beta s), are a group of structurally related proteins whic h have been shown to stimulate bone formation in vivo. Since these pro teins are concentrated in the organic matrix of bone and would be rele ased during bone resorption, they are likely to have a profound effect on the remodeling bone and may provide a link between bone resorption and bone formation, We are using primary cultures of fetal rat calvar ial cells (FRCC) to study the independent and combined effects of OP-1 /BMP-7 and TGF-beta 1 on bone cells at different stages of differentia tion in order to identify responding cell populations and target genes . We have confirmed prior reports that OP-1 stimulates, while TGF-beta 1 inhibits, osteogenic differentiation in this system, The increase i n both number and size of the mineralized nodules induced by OP-1 was accompanied by increased expression of alkaline phosphatase and type I collagen with an induction of bone sialoprotein (BSP) suggesting that OP-1 stimulates both differentiation and clonal expansion of osteobla stic cells, Interestingly, TGF-beta 1 abrogated OP-1 induced nodule fo rmation, Despite these opposing effects on osteogenic differentiation, TGF-beta 1 (Wrana et al, 1991) and OP-1 both stimulated a rapid induc tion of osteopontin (OPN) mRNA in confluent FRCC cultures enriched in pre-osteoblastic cells, In contrast, when OP-1 was added to nodule-for ming cultures which are enriched in osteoblastic cells, there was only a weak induction of OPN, Moreover, while the expression of one marker for mature osteoblasts (BSP) was refractory to OP-1, another (osteoca lcin) was markedly stimulated, Thus OP-1 has selective effects on bone matrix protein expression that are dependent on the differentiated st ate of the cells.