The effects of aging on the bone inductive activity of recombinant human bone morphogenetic protein-2.
We examined the effects of gain 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 micrograms 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 micrograms rhBMP-2 for 12 days, 3-month-old rats required 30 micrograms rhBMP-2, whereas 16-month-old rats required 60 micrograms. Treatment with either GH or 1,25-dihydroxyvitamin D3 during the 12-day implantation period returned the bone formation in 16-month-olds rats to that in 3-month-old rats. These studies show that aging blunts rhBMP-2 inducted 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 order rats or to a change in the responsiveness of these target cells to rhBMP-2.
Fleet
J C
JC
Mineral Bioavailability Laboratory, U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University Boston, Massachusetts 02111, USA.
Cashman
K
K
Cox
K
K
Rosen
V
V
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001846:Bone Development / Q000187:drug effects / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology; D006801:Humans; D015675:Osteocalcin / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004343:Drug Implants; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D015675:Osteocalcin; D013006:Growth Hormone; D002117:Calcitriol