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Basic fibroblast growth factor-heparan sulphate complex in the human dialysis-related amyloidosis
1Department of Internal Medicine, Branch Hospital of Nagoya University, School of Medicine, Japan.
Abstract:
A major constituent of the amyloid fibrils in dialysis-related amyloidosis is beta 2-microglobulin (beta 2-MG). Heparan sulphates (HS) co-localize with the amyloid fibrils and monocytes/macrophages are commonly found around amyloid deposits, but the role of HS in amyloidogenesis is not yet defined. HS have variable saccharide sequences and can interact specifically with basic fibroblast growth factor (bFGF), a potent chemotactic factor for the monocyte/macrophage. The present investigation was undertaken to look for a functional link between co-localized HS and the pathogenesis of dialysis-related amyloidosis. Using amyloid-enriched ligament, immunohistochemical localization was tested for beta 2-MG, endogenous bFGF, and bFGF-binding portions of HS. For the detection of bFGF-binding portions of HS, the ligament sections were incubated with exogenous bFGF and then with anti-bFGF antibody. The specificity of the interaction between bFGF and HS was established by confirming a concomitant loss of immunoreactivity during selective removal of HS with heparitinase. beta 2-MG, endogenous bFGF, and bFGF-binding portions of HS were detected between bundles of collagen. Endogenous bFGF and bFGF-binding portions of HS were not detected in more advanced amyloid lesions, whereas beta 2-MG and other portions of HS were detected. We propose that beta 2-MG, endogenous bFGF, and bFGF-binding portions of HS form a complex and localize in the early amyloid lesions of dialysis-related amyloidosis.
Insights
Beta 2-microglobulin (beta 2-MG) forms amyloid fibrils in dialysis-related amyloidosis. This study suggests beta 2-MG, basic fibroblast growth factor (bFGF), and heparan sulfates (HS) form early complexes in dialysis-related amyloidosis.
Area of Science:
- Biochemistry
- Immunohistochemistry
- Pathology
Background:
- Dialysis-related amyloidosis (DRA) is characterized by beta 2-microglobulin (beta 2-MG) amyloid fibrils.
- Heparan sulfates (HS) are found with amyloid deposits and monocytes/macrophages in DRA.
- The specific role of HS in the pathogenesis of DRA remains undefined.
Purpose of the Study:
- To investigate a functional link between HS and the pathogenesis of dialysis-related amyloidosis.
- To explore the potential interaction between beta 2-MG, HS, and basic fibroblast growth factor (bFGF) in DRA.
Main Methods:
- Immunohistochemical localization of beta 2-MG, endogenous bFGF, and bFGF-binding HS portions in amyloid-enriched ligament.
- Incubation of ligament sections with exogenous bFGF followed by anti-bFGF antibody to detect bFGF-binding HS.
- Selective removal of HS using heparitinase to confirm the specificity of bFGF-HS interaction.
Main Results:
- Beta 2-MG, endogenous bFGF, and bFGF-binding HS were detected within collagen bundles in early lesions.
- Endogenous bFGF and bFGF-binding HS were absent in advanced amyloid lesions.
- Beta 2-MG and other HS portions were present in both early and advanced lesions.
Conclusions:
- A complex of beta 2-MG, endogenous bFGF, and bFGF-binding HS likely forms and localizes in early amyloid lesions of DRA.
- This complex may play a role in the initial stages of dialysis-related amyloidosis pathogenesis.
- Further research is needed to elucidate the precise mechanisms of HS involvement in DRA.