Cartilage biomarkers in hemodialysis patients and the effect of β 2-microglobulin on articular chondrocytes

Abstract

Dialysis-related amyloidosis (DRA) is a severe complication of maintenance hemodialysis (HD). Given the predominant deposition of beta(2)-microglobulin (beta2m) fibrils on articular cartilage in early DRA, we investigated the significance of beta2m and its relationship to distinct cartilage biomarkers in early DRA diagnosis in HD patients. Furthermore, we assessed the effects of beta2m on articular chondrocytes in vitro. Serum samples from 133 patients were collected before and after HD. Type II collagen cleavage product (C2C), procollagen II c-propeptide (CPII), aggrecan chondroitin sulfate 846 epitope (CS-486) and cartilage oligomeric matrix protein (COMP) levels were determined by enzyme-linked immunosorbent assay. Primary bovine articular chondrocytes were cultured as monolayers and incubated with beta2m at 1.5mg/l and 20mg/l. Cartilage glucosaminoglycan synthesis was measured by [(35)S]sulfate incorporation. mRNA expression of interleukin (IL)-1beta, matrix metalloproteinases (MMPs)-3 and -9 was measured by reverse-transcriptase polymerase chain reaction (RT-PCR). Incubation with beta2m at 20mg/l significantly decreased matrix biosynthesis. PCR analysis revealed an increase of IL-1beta, as well as MMPs-3 and -9 on the mRNA level. C2C/CPII, CS-486 and COMP levels were increased only in a subset of patients without a significant correlation with beta2m concentrations. A subgroup analysis elucidated an increase in type II collagen degradation during the first years of HD, as shown by the elevation of C2C/CPII ratio. beta2m exerted anti-anabolic effects on articular chondrocytes in vitro and might be involved in cartilage degradation in HD patients. beta2m serum levels, however, did not reflect cartilage degradation in DRA. The assessment of C2C/CPII, CS-486 or COMP concentrations apparently has minor relevance in DRA diagnosis in HD patients. However, the increased type II collagen breakdown within 5 years after HD onset possibly mirrors the early stages of DRA. Thus, the C2C/CPII ratio could be employed in longitudinal studies, since it may reflect a risk for DRA related arthropathy development in a subset of patients.