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Transforming growth factor-beta1 (TGF-beta1) has opposite effects on osteoblastic cells in vitro, namely an inhibitory or stimulatory effect on cell differentiation. Because these effects are dependent on TGF-beta1 concentration or culture condition, we investigated whether the in vivo effects of TGF-beta1 on bone formation in infant rat calvaria were affected by the dose or the injection site. Human platelet-derived TGF-beta1 was injected subcutaneously onto the periosteal surface of parietal bone of 4-week-old rats at doses of 5 or 20ng/100microl per animal for 14 days, and the local effect on bone formation was examined by bone histomorphometry. TGF-beta1 treatment for 7 days decreased the mineral apposition rate, bone formation rate, and elongated mineralization lag time at the injection site. This change became more prominent when treatment continued for 14 days. These changes were restricted to the TGF-beta1-exposed area. Multiple subcutaneous injections of a relatively high dose (200ng/100microl per animal) of TGF-beta1 induced woven bone formation, in addition to marked inhibition of bone formation rate and prolongation of mineralization lag time. On the other hand, direct exposure of TGF-beta1 in the subperiosteal layer induced woven bone with periosteal cell proliferation even at a single injection of a low dose (5 or 50ng/25 microl) of TGF-beta1. In conclusion, the in vivo effects of TGF-beta1 on bone formation varied depending on its concentration and injection site. Also, subcutaneous injection of relatively low doses of TGF-beta1 inhibited local lamellar bone formation.

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Oral treatment with a new bisphosphonate, YM175, for 13 wk resulted in increased bone tissue mass by both intramembranous and endochondral ossification processes in adult beagle dogs. Intramedullary bone formation due to intramembranous process was observed in dogs treated with a highly toxic dose of YM175. The newly formed woven bone trabeculae, showing immature to relatively mature figures, were present between the preexisting cancellous bone. The immature bone consisted of spindle-shaped mesenchymal cells with osteoid tissues. Many active osteoblasts surrounded the immature woven bone, while only few osteoclasts were seen on the surfaces of the new bone. Endochondral bone change was observed at the costochondral junction in all YM175-treated groups. Accumulation of unresorbed mineralized cartilage with its covering of bone at this site resulted in an increase in length of the area of primary spongiosa. Although the endochondral bone change induced by YM175 was due to a bisphosphonate-induced inhibitory effect on bone resorption, the intramedullary bone formation is unique to YM175.

We investigated early local changes induced by recombinant human bone morphogenetic protein (rhBMP)-2 and a novel carrier, poly[L-lactide-co-glycolide] copolymer-coated gelatin sponge (PGS). A 1.5 cm segmental bone defect was created in the diaphysis of the right ulna of male Japanese white rabbit. Defects received PGS with or without rhBMP-2 (0, 0.4, or 1 mg/cm3) and were harvested at 3, 7, 14, 21, or 28 days post implantation for histological examination. Immuno-staining for vascular endothelial growth factor (VEGF) was also performed. Spindle-shaped cells were observed in the rhBMP-2-treated groups 3 and 7 days after implantation. Bone regeneration was detected after 14 days in the rhBMP-2-treated groups and the bone area increased with time and dose. Expression of VEGF was observed in all groups at 3 days and was maintained by 14 days only in the defects treated with rhBMP-2 at a dose of 1 mg. These results indicate that rhBMP-2 exert its osteo-inductive activities via the promotion of osteogenic cell mobilization, and possibly via angiogenesis based on VEGF induction. Foreign-body reactions to the implanted PGS were similar to those observed when either poly[L-lactide-co-glycolide] copolymer or gelatin was individually implanted. These results indicate that the PGS is a useful and safe carrier for rhBMP-2.

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