A representative, water-soluble middle sized molecule, β
2-m (11.8 kDa), is associated with survival in dialysis patients [
6‐
8]. For example, the randomized Hemodialysis (HEMO) Study showed that predialysis serum β
2-m levels were associated with all-cause mortality [
8], as well as mortality owing to infections in dialysis patients [
9]. In CKD-related osteoarticular disorders, β
2-m is a precursor protein for DRA [
10]. β
2-m-related amyloid fibrils are formed and deposited primarily in osteoarticular joint tissues, resulting in various osteoarticular disorders, such as carpal tunnel syndrome, destructive spondyloarthropathy, and bone cysts in dialysis patients [
11]. Accumulation of β
2-m and the interactions between β
2-m and other biological molecules are thought to be needed for amyloid fibril formation in vivo [
12,
13]. The β
2-m-related amyloid fibril formation and extension occurs according to a nucleation-dependent polymerization model [
12,
14]. This model consists of a nucleation phase and an extension phase. Nucleus formation requires a series of monomer association steps, which represent the rate-limiting step in amyloid fibril formation. Once the nucleus (
n-mer) has been formed, further addition of monomers becomes thermodynamically favorable, resulting in the rapid extension of amyloid fibrils according to a first-order kinetic model [
12,
14]. In the mechanism of amyloidogenesis of natively folded proteins as well as β
2-m, partial unfolding is believed to be a prerequisite to assembly into amyloid fibrils, both in vitro and in vivo. In this process, conformational change of β
2-m with biological molecules is necessary [
12,
15]. The extension of β
2-m-related amyloid fibrils, as well as the formation of the fibrils from β
2-m, is greatly dependent on the pH of the reaction mixture, with the optimum pH being around 2.0–3.0 [
15,
16]. On the other hand, the fibrils readily depolymerize into monomeric β
2-m at pH 7.5 [
17]. Thus, to observe the extension of β
2-m-related amyloid fibrils at neutral pH, we need to unfold the compact structure of β
2-m monomer to an amyloidogenic conformer, and stabilize the extended fibrils by adding other factors. We investigated the effect of low concentrations of 2,2,2-trifluoroethanol (TFE) and sodium dodecyl sulfate (SDS) on the extension of β
2-m-related amyloid fibrils at neutral pH in vitro [
18,
19]. TFE at concentrations of up to 20% (v/v) or SDS at a critical micelle concentration caused amyloid fibril extension by inducing a subtle change in the tertiary structure of β
2-m, and stabilizing the fibrils at neutral pH. TFE-induced amyloid fibril extension at neutral pH was enhanced by several kinds of glycosaminoglycans, especially heparin [
18]. In these reactions, glycosaminoglycans bound directly to the amyloid fibrils. In another study, depolymerization of amyloid fibrils at pH 7.5 was inhibited dose-dependently by the presence of apolipoprotein E, some glycosaminoglycans, or proteoglycans [
17,
20]. The results suggested that those biological molecules could enhance the deposition of β
2-m-related amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of β
2-m in the fibrils [
12]. Using an in vitro β
2-m amyloid fibril formation model, other studies showed that several other biological molecules including lysophospholipids [
21] and various non-esterified fatty acids [
22] are enhancing-factor candidates for β
2-m-related amyloid fibril deposition in vivo. Thus, deposition of β
2-m-related amyloid requires β
2-m conformational change and stabilization of amyloid fibrils with some biological molecules (Fig.
1). In contrast, recent findings showed that extracellular chaperones including α
2-macroglobulin may inhibit amyloid fibril formation by capturing unfolded and misfolded β
2-m [
23]. Further clinical studies will be needed to verify the in vivo roles of these molecules in DRA. The β
2-m-related amyloid fibrils deposited in tissues induce cellular interactions that are associated with DRA symptoms, such as carpal tunnel syndrome and destructive spondyloarthropathy. When synovial fibroblast cells were reacted with extended β
2-m-related amyloid fibrils in vitro, cellular survival were impaired by disrupting endosomal/lysosomal membranes [
24]. This reaction may be associated with the development of carpal tunnel syndrome in CKD patients. Macrophages in spine lesions are thought to be activated by deposited amyloid fibrils, and activated macrophages may accelerate destruction of spine with long-term dialysis treatment [
25].