β2-microglobulin stimulates osteoclast formation

Dialysis-related amyloidosis is a complication of long-term chronic kidney disease ( CKD) resulting in deposition of beta(2)- microglobulin ( beta M-2) amyloid in osteoarticular tissue. Clinical manifestations include destructive arthropathy, bone cysts, and fractures. Since osteolytic lesions are prominent findings around the beta M-2 deposits, we sought evidence whether beta M-2 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 beta M-2. Osteoprotegerin was unable to block this osteoclastogenic effect of beta M-2 Osteoblasts or stromal cells were not necessary to induce this osteoclastogenesis, as formation was induced by incubating beta M-2 with colony-forming unit granulocyte macrophages ( the earliest identified precursor of osteoclasts) or the murine RAW 264.7 monocytic cell line. beta M-2 Upregulated tumor necrosis factor-alpha (TNF-alpha) and IL-1 expression in a dose-dependent manner; however, a TNF-alpha-neutralizing antibody blocked beta M-2- induced osteoclast formation. These results show that beta M-2 stimulates osteoclastogenesis, supporting its direct role in causing bone destruction in patients with CKD.