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Beta 2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts
W F Owen1, F F Hou, R O Stuart
1Department of Medicine, Brigham & Women's Hospital Harvard Medical School, Boston, Massachusetts, USA. wfowen@bics.bwh.harvard.edu
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.
Insights
Advanced glycation end products (AGEs) on beta 2-microglobulin (beta 2m) reduce collagen synthesis in fibroblasts. This process involves the receptor for AGE (RAGE) and epidermal growth factor (EGF), impacting connective tissue and bone remodeling.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Beta 2-microglobulin amyloidosis (A beta 2m) is a complication of long-term dialysis.
- Beta 2-microglobulin modified with advanced glycation end products (beta 2m-AGE) is a key amyloid component.
- The role of beta 2m-AGE in A beta 2m pathogenesis is unclear, but it localizes to collagen-rich tissues.
Purpose of the Study:
- To investigate the role of beta 2m-AGE in fibroblast collagen synthesis.
- To determine if fibroblasts are a target for beta 2m-AGE action.
- To elucidate the signaling pathway involved in beta 2m-AGE effects on connective tissue.
Main Methods:
- Exposure of human fibroblast cell lines to beta 2m-AGE and AGE-modified albumin.
- Measurement of procollagen type I mRNA and type I collagen synthesis.
- Use of antibodies against the receptor for AGE (RAGE) and epidermal growth factor (EGF) to block specific pathways.
Main Results:
- Beta 2m-AGE significantly decreased procollagen type I mRNA and type I collagen synthesis in fibroblasts.
- AGE-modified albumin produced similar inhibitory effects.
- Antibodies against RAGE and EGF partially blocked the inhibitory effects, indicating RAGE mediation and EGF involvement.
Conclusions:
- Beta 2m-AGE actively participates in connective tissue and bone remodeling.
- The mechanism involves fibroblast RAGE and the growth factor EGF as an intermediate mediator.
- These findings highlight a potential therapeutic target for A beta 2m-related complications.