β2-Microglobulin stimulates osteoclast formation

Dialysis-related amyloidosis is a complication of long-term chronic kidney disease (CKD) resulting in deposition of β2-microglobulin (β2M) amyloid in osteoarticular tissue. Clinical manifestations include destructive arthropathy, bone cysts, and fractures. Since osteolytic lesions are prominent findings around the β2M deposits, we sought evidence whether β2M causes bone destruction by directly stimulating osteoclast activity and if this was mediated by local cytokine production. A dose-dependent increase in the number of tartrate-resistant alkaline phosphatase-positive multinucleated cells was found in cultured mouse marrow cells treated with β2M. Osteoprotegerin was unable to block this osteoclastogenic effect of β2M. Osteoblasts or stromal cells were not necessary to induce this osteoclastogenesis, as formation was induced by incubating β2M with colony-forming unit granulocyte macrophages (the earliest identified precursor of osteoclasts) or the murine RAW 264.7 monocytic cell line. β2M Upregulated tumor necrosis factor-α (TNF-α) and IL-1 expression in a dose-dependent manner; however, a TNF-α-neutralizing antibody blocked β2M-induced osteoclast formation. These results show that β2M stimulates osteoclastogenesis, supporting its direct role in causing bone destruction in patients with CKD.