Abstract
The formation of insoluble amyloid fibrils is associated with an array of devastating human diseases. Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in the progressive destruction of the bones and joints. Elevated concentrations of β2-microglobulin (β2m) in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in the osteoarticular tissues, but the cellular basis for the destruction of these tissues in DRA is poorly understood. In this study we performed a systematic analysis of the interaction of monomeric and fibrillar β2m with primary human cells of the types present in the synovial joints of subjects with DRA. Building upon observations that macrophages infiltrate β2m amyloid deposits in vivo we demonstrate that monocytes, the precursors of macrophages, cannot degrade β2m fibrils, and that both monomeric β2m and fibrillar β2m are cytotoxic to these cells. β2m fibrils also impair the formation of bone resorbing osteoclasts from monocytes and reduce the viability of osteoblasts, the cell type that produces bone. As a consequence, we predict that β2m amyloid will disrupt the remodelling of the bone, which is critical for the maintenance of this tissue. Moreover, we show that β2m fibrils reduce the viability of chondrocytes, rationalizing the loss of cartilage in DRA. Together, our observations demonstrate that β2m cytotoxicity has multiple cellular targets in the osteoarticular tissues and is likely to be a key factor in the bone and joint destruction characteristic of DRA.
Highlights
The formation of insoluble amyloid fibrils is associated with a spectrum of devastating human diseases, many of which are characterised by tissue destruction [1]
The resultant fibrils were not recognized by the A11 antibody, were recognized by the WO1 antibody (Fig. 1C); bound the amyloid specific dye thioflavin-T (Fig. 1D) and exhibited a long straight morphology when visualized by negative stain transmission electron microscopy (TEM) (Fig. 1E) reminiscent of ex vivo b2m amyloid [34,35,36]
In order to elucidate the cellular basis for the pathological consequences in dialysis-related amyloidosis (DRA) we performed a systematic analysis of the effects of b2m fibrils and monomeric b2m on cell types that are present in the synovial joints of subjects with DRA
Summary
The formation of insoluble amyloid fibrils is associated with a spectrum of devastating human diseases, many of which are characterised by tissue destruction [1] One such disorder is dialysis-related amyloidosis (DRA), a debilitating complication of long-term hemodialysis [2,3]. The normal serum concentration of b2m is 1–3 mg/ml but, in end stage renal disease, neither the kidney nor the dialysis membrane can efficiently remove b2m from the circulation and serum levels increase by up to 60 fold and can exceed 100 mg/ml [2,3,7]. B2m forms amyloid fibrils in the osteoarticular tissues resulting in arthropathy, cartilage destruction, bone cysts leading to pathologic fractures, carpal tunnel syndrome and spondyloarthropathy [2,3,4,5,6,8,9]
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