Inhibition of matrix-induced bone differentiation by advanced glycation end-products in rats.
Glycation of long-lived proteins is an inevitable consequence of aging that is accelerated in patients with diabetes mellitus. Treatment of demineralized bone matrix particles from 35-week-old normal Long-Evans rats with glycoaldehyde, a precursor of advanced glycation end-products, was used to assess the effects of bone-matrix glycation on the process of bone differentiation. Matrix was incubated in phosphate buffered saline alone, phosphate buffered saline containing glycolaldehyde, glycolaldehyde plus the advanced glycation product-inhibitor aminoguanidine, or glycolaldehyde plus the advanced glycation product-inhibitor sodium cyanoborohydride. Glycolaldehyde increased the matrix advanced glycation product content as measured by specific fluorescence more than two-fold, while inhibiting bone differentiation more than 90% as measured by in vivo 45CaCl2 uptake, alkaline phosphatase levels, and histology. In contrast, simultaneous incubation with the advanced glycation product-inhibitor aminoguanidine or sodium cyanoborohydride not only reduced fluorescence to normal, but also restored bone differentiation. Furthermore, the inhibition of bone differentiation by glycolaldehyde was not reversed by subsequent application of recombinant bone morphogenetic protein-2. These observations suggest that formation of advanced glycation products on bone matrix alters its ability to induce bone formation, and probably involves alterations of binding sites for extractable proteins with direct bone inductive properties such as bone morphogenetic protein-2. Decreased bone formation associated with aging and diabetes may result, in part, from advanced glycation product formation on matrix proteins.
Fong
Y
Y
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
Edelstein
D
D
Wang
E A
EA
Brownlee
M
M
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001857:Bone Matrix / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D019485:Bone Morphogenetic Proteins; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects; D001894:Borohydrides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006133:Growth Substances / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology; D051381:Rats
D019485:Bone Morphogenetic Proteins; D001894:Borohydrides; D017127:Glycation End Products, Advanced; D006133:Growth Substances; D006146:Guanidines; D011506:Proteins; C009282:sodium cyanoborohydride; D000469:Alkaline Phosphatase; D000079:Acetaldehyde; C004479:pimagedine; D002118:Calcium; C010972:glycolaldehyde