Beta2-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(2)M) amyloid in osteoarticular tissue. Clinical manifestations include destructive arthropathy, bone cysts, and fractures. Since osteolytic lesions are prominent findings around the beta(2)M deposits, we sought evidence whether beta(2)M 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(2)M. Osteoprotegerin was unable to block this osteoclastogenic effect of beta(2)M. Osteoblasts or stromal cells were not necessary to induce this osteoclastogenesis, as formation was induced by incubating beta(2)M with colony-forming unit granulocyte macrophages (the earliest identified precursor of osteoclasts) or the murine RAW 264.7 monocytic cell line. beta(2)M Upregulated tumor necrosis factor-alpha (TNF-alpha) and IL-1 expression in a dose-dependent manner; however, a TNF-alpha-neutralizing antibody blocked beta(2)M-induced osteoclast formation. These results show that beta(2)M stimulates osteoclastogenesis, supporting its direct role in causing bone destruction in patients with CKD.
Menaa
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C
Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois 60201, USA.
Esser
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E
Sprague
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SM
D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000150:complications / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D015870:Gene Expression / Q000187:drug effects; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D006435:Renal Dialysis / Q000009:adverse effects; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism* / Q000494:pharmacology
D000906:Antibodies; D039661:Integrin beta3; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D053245:RANK Ligand; D018003:Receptors, Calcitonin; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium