Advanced glycation endproducts interfere with integrin-mediated osteoblastic attachment to a type-I collagen matrix

Abstract

The adhesion of osteoblasts to bone extracellular matrix, of which type-I collagen constitutes >85%, can modulate diverse aspects of their physiology such as growth, differentiation and mineralisation. In this study we examined the adhesion of UMR106 rat osteoblast-like cells either to a control (Col) or advanced-glycation-endproduct-modified (AGEs-Col) type I collagen matrix. We investigated the possible role of different integrin receptors in osteoblastic adhesion, by co-incubating these cells either with beta-peptide (conserved sequence 113-125 of the beta subunit of integrins) or with two other peptides, RGD (Arg-Gly-Asp) and DGEA (Asp-Gly-Glu-Ala), which are recognition sequences for the alpha-subunits of alpha(1,5)beta(1) and alpha(2)beta(1) integrins. Collagen glycation inhibited the adhesion of UMR106 osteoblasts to the matrix (40% reduction versus Col, P > 0.001). beta-Peptide showed a dose- and glycation-dependent inhibitory effect on adhesion, and at a concentration of 100 microM decreased the attachment of UMR106 cells to both matrices (42% to Col, P<0.001and 25% to AGEs-Col, P<0.01). The synthetic peptides RGD (1mM) and DGEA (5mM) inhibited the attachment of UMR106 cells to Col (30 and 20%, P > 0.01 and P< 0.001, respectively), but not to AGEs-Col. beta-Peptide induced an increase in UMR106 cell clumping and a decrease in cellular spreading, while DGEA increased spreading with cellular extensions in multiple directions. These results indicate that both alpha and beta integrin subunits participate in osteoblastic attachment to type-I collagen, probably through the alpha(1,5)beta(1) and alpha(2)beta(1) integrins. AGEs-modification of type-I collagen impairs the integrin-mediated adhesion of osteoblastic cells to the matrix, and could thus contribute to the pathogenesis of diabetic osteopenia.

Bone mineral density and hip structural analysis in type 1 diabetic men

“…Increasing evidence suggests that insulin deficiency in type 1 diabetes may interfere with new bone formation, possibly due to defective function of osteoblasts. The impaired recruitment and function of osteoblasts might be an effect of increased osmolarity in poorly controlled diabetes (29), lower levels of insulin-like growth factor I (30), or accumulation of advanced glycation end-products in the type I collagen matrix (31). Earlier theory on the link between diabetic osteopenia and bone marrow microangiopathy (32) has not been confirmed in other studies.…”

Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy

“…Although glucose does not react with arginine residues directly, it may contribute as a source of reactive carbonyl species formed during glycoxidative reactions, which may, in turn, modify arginine. Interestingly, incubation of collagen I with ribose, a sugar prone to rapid oxidative degradation, caused inhibition of osteoblast adhesion to this matrix protein (60). However, in vivo glucose autoxidation may play a secondary role in inhibition of cell-matrix interactions because glyoxal is the only ␣-dicarbonyl compound formed in this reaction (13).…”

Roles of gap junctions and hemichannels in bone cell functions and in signal transmission of mechanical stress

“…Fluid flow stimulates pathways that are regulated by integrin binding to the extracellular matrix (182). Among various isotypes of integrins, α5 and β1 integrins are expressed in virtually all cell types in bone (183)(184)(185) and cartilage (186), and are found to induce responses to mechanical stimuli (181). Integrins, α2, α5 and β1 induce ERK activation in osteocytic cells (187).…”