¹Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois, USA

Correspondence: SM Sprague, Division of Nephrology and Hypertension, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, Illinois 60201, USA. E-mail: ssprague@northwestern.edu

Received 2 July 2007; Revised 23 December 2007; Accepted 24 January 2008; Published online 26 March 2008.

Abstract

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