Abstract
BackgroundThe tissue accumulation of protein-bound advanced glycation endproducts (AGE) may be involved in the etiology of diabetic chronic complications, including osteopenia. The aim of this study was to investigate the effect of an AGE-modified type I collagen substratum on the adhesion, spreading, proliferation and differentiation of rat osteosarcoma UMR106 and mouse non-transformed MC3T3E1 osteoblastic cells. We also studied the role of reactive oxygen species (ROS) and nitric oxide synthase (NOS) expression on these AGE-collagen mediated effects.ResultsAGE-collagen decreased the adhesion of UMR106 cells, but had no effect on the attachment of MC3T3E1 cells. In the UMR106 cell line, AGE-collagen also inhibited cellular proliferation, spreading and alkaline phosphatase (ALP) activity. In preosteoblastic MC3T3E1 cells (24-hour culture), proliferation and spreading were significantly increased by AGE-collagen. After one week of culture (differentiated MC3T3E1 osteoblasts) AGE-collagen inhibited ALP activity, but had no effect on cell number. In mineralizing MC3T3E1 cells (3-week culture) AGE-collagen induced a decrease in the number of surviving cells and of extracellular nodules of mineralization, without modifying their ALP activity. Intracellular ROS production, measured after a 48-hour culture, was decreased by AGE-collagen in MC3T3E1 cells, but was increased by AGE-collagen in UMR106 cells. After a 24-hour culture, AGE-collagen increased the expression of endothelial and inducible NOS, in both osteoblastic cell lines.ConclusionsThese results suggest that the accumulation of AGE on bone extracellular matrix could regulate the proliferation and differentiation of osteoblastic cells. These effects appear to depend on the stage of osteoblastic development, and possibly involve the modulation of NOS expression and intracellular ROS pathways.
Highlights
The tissue accumulation of protein-bound advanced glycation endproducts (AGE) may be involved in the etiology of diabetic chronic complications, including osteopenia
The formation of AGE-products on the collagenous matrix caused no effect on the adhesion of nontransformed MC3T3E1 cells
The relatively different osteoblastic response to AGE-collagen which we report in the present study, may be a consequence of the signal transduction mechanisms induced by the occupancy of AGE-receptors, and be mediated by integrin or growth factor receptors, which are intimately associated with the process of osteoblast growth and differentiation
Summary
The tissue accumulation of protein-bound advanced glycation endproducts (AGE) may be involved in the etiology of diabetic chronic complications, including osteopenia. Recent research indicates that an increase in the steadystate levels of highly reactive dicarbonylic compounds ("carbonyl stress") may lead to the formation of advanced glycation endproducts or AGE. These AGE products could be involved in the etiology of the long-term complications of several human afflictions, such as Diabetes mellitus, ageing, uremia and Alzheimer's disease [1,2]. In diabetic patients with long-standing hyperglycemia, an increase in the generation of AGE products can be partly explained by the process of non-enzymatic glycosylation of proteins. Most studies have demonstrated that AGE can induce structural and functional alterations of various proteins
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