The effects of aging on the bone inductive activity of recombinant human bone morphogenetic protein-2

We examined the effects of aging on the ectopic bone-forming ability of recombinant human BMP-2 (rhBMP-2) in rats and investigated the mechanism by which aging might affect this type of bone. Bone formation induced after 12 days of sc implantation of 5 mu g rhBMP-2 was reduced as animals aged from 1-16 months. The osteocalcin messenger RNA levels of implants also declined in aging animals. When the implant period was doubled, 16-month-old rats formed amounts of bone equivalent to those in 3-month-old rats. Increasing the dose of rhBMP-2 increased bone formation in older rats. To get a response comparable to that seen in 1-month-old rats given 5 mu g rhBMP-2 for 12 days, 3-month-old rats required 30 mu g rhBMP-2, whereas 16-month-old rats required 60 mu g. Treatment with either GH or 1,25-dihydroxyvitamin D-3 during the 12-day implantation period returned the bone formation in 16-month-old rats to that in 3-month-old rats. These studies show that aging blunts rhBMP-2-induced bone formation in rats. We speculate that the decreased response may be due in part to a decrease in the number of mesenchymal stem cells present in older rats or to a change in the responsiveness of these target cells to rhBMP-2.