β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts

Abstract

Beta 2-microglobulin amyloidosis (A beta 2m) is a serious complication for patients undergoing long-term dialysis. beta 2-microglobulin modified with advanced glycation end products (beta 2m-AGE) is a major component of the amyloid in A beta 2m. It is not completely understood whether beta 2m-AGE plays an active role in the pathogenesis of A beta 2m, or if its presence is a secondary event of the disease. beta 2-microglobulin amyloid is mainly located in tendon and osteo-articular structures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of collagen. Recent identification of AGE binding proteins on human fibroblasts lead to the hypothesis that the fibroblast may be a target for the biological action of beta 2m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen type I mRNA and type I collagen synthesis after exposure to beta 2m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor for AGE, attenuated this decrease in synthesis, indicating that the response was partially mediated by RAGE. In addition, antibody against epidermal growth factor (EGF) attenuated the decrease in type I procollagen mRNA and type I collagen induced by beta 2m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that beta 2m-AGE actively participates in connective tissue and bone remodeling via a pathway involving fibroblast RAGE, and at least one interposed mediator, the growth factor EGF.

Advanced Glycation End Products Enhance Expression of Pro-apoptotic Genes and Stimulate Fibroblast Apoptosis through Cytoplasmic and Mitochondrial Pathways

“…By use of a blocking antibody, it was shown that virtually all of the apoptotic effect of AGEs on fibroblast apoptosis was mediated through the RAGE. Previously, it was shown that RAGE activation reduces collagen production in fibroblasts (34). In addition, it has been reported that blocking RAGE significantly enhances wound healing in diabetes (35).…”

“…However, AGEs in connective tissue can have detrimental effects through cell signaling. For example, RAGE activation in dermal fibroblasts reduces collagen synthesis and matrix production (34). AGEs also contribute to impaired diabetic wound healing, in part through interfering with formation of an extracellular matrix (35).…”

The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition

“…In contrast, the inhibition of AGE-RAGE formation by blocking RAGE resulted in faster wound repair and regeneration [40]. Similarly, the presence of AGE-RAGE complex on fibroblasts reduced the formation of collagen as a necessary compound for wound repairing [41]. The negative effect of AGE-RAGE on wound healing has been stated in animal studies using application of exogenous AGEs [16,42].…”

The relationship of oral disturbances of diabetes mellitus patients with paraoxonase gene polymorphisms

“…The decrements in inflamatory responses may affect the resistance to infections, so this will also contribute to the tissue destructions. [3][4][5] As DM is a multisystemic disorder, diabetic patients may also have serious problems with their oral cavity. This is thought to be especially associated with microangiopathic complications that are effective in several other tissues.…”