RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2 ENHANCES EXPRESSION OFINTERLEUKIN-6 AND TRANSFORMING GROWTH-FACTOR-BETA-1 GENES IN NORMAL HUMAN OSTEOBLAST-LIKE CELLS

The process of recombinant human bone morphogenetic protein-2 (rhBMP-2 )-induced endochondral ossification involves 1) the proliferation and differentiation of mesenchymal cells into chondroblasts and osteoblast s; 2) the production and maturation of cartilage and bone matrix; and 3) the differentiation of circulating osteoclast precursor cells into osteoclasts. Currently the molecular mechanisms of these complex seque ntial events are unknown. It seemed reasonable to us to assume that co mmunication between cells through soluble mediators during bone induct ion by rhBMP-2 may play an important role in the sequential differenti ation of chondroblasts, osteoblasts, and osteoclasts. We have therefor e used a human osteoblast-like initial transfectant cell line (HOBIT) to study the effect of rhBMP-2 on gene expression of interleukin-6 (IL -6) and transforming growth factor-beta1 (TGF-beta1), both of which af fect osteogenesis and ostoeclastogenesis. Our results have demonstrate d that rhBMP-2 acts on HOBIT cells to stimulate expression of IL-6 and TGF-beta1 genes and the production of IL-6. Enhancement of gene expre ssion of IL-6 and TGF-beta1 by rhBMP-2 was both sensitive (half maxima l effect at approximately 10 ng/ml) and potent (maximum induction was approximately four and threefold greater than controls, respectively). Time course studies showed that the induction of TGF-beta1 and IL-6 m RNA occurs within short periods-4 and 8 hours after exposure to rhBMP- 2, respectively. Interestingly, these effects, however, were not accom panied by the mitogenic action of rhBMP-2. It suggests that rhBMP-2 en hances IL-6 and TGF-beta1 production during osteogenesis and at least in part mediates the complex sequential differentiation of chondroblas ts, osteoblasts, and osteoclasts during rhBMP-2-induced endochondral o ssification. (C) 1994 Wiley-Liss, Inc.