The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease

Background: Osteoclasts are multinucleated cells (MNCs) that form from circulating mononuclear precursors in the presence of the receptor activator of nuclear factor kappaB-ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Aim: To determine whether cytokines and growth factors influence RANKL/M-CSF induced osteoclastogenesis and bone resorption in Paget's disease. Design: Prospective case-control study. Methods: Serum levels of M-CSF, interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNFalpha) were measured in 13 Paget's disease patients and 8 normal controls. The effect of serum from Paget's patients on osteoclast formation was also assessed. Results: Serum levels of IL-1beta, IL-6 and TNFalpha were low or undetectable in Paget's disease patients and normal controls. Levels of M-CSF were significantly increased in Paget's patients who were not currently under treatment. In Paget's patients under treatment, serum M-CSF levels were not significantly different from normal controls. The addition of serum from untreated Paget's patients dose-dependently increased RANKL-induced osteoclast formation and lacunar resorption in normal monocyte cultures; elevated IL-6 levels were found in the supernatant and the addition of a specific antibody to human IL-6 blocked the increase in osteoclast formation and resorption. Serum from untreated Paget's patients also induced osteoclast formation in the absence of exogenous M-CSF; an antibody specific to human M-CSF abolished this effect. Discussion: Both M-CSF and IL-6 play a major role in osteoclast formation and bone resorption in Paget's disease and measurement of serum M-CSF may provide a useful indicator of disease activity.