SAT0062 The role of osteoclast formation in the pathogenesis of osteoporosis in rheumatoid arthritis

Abstract

Background Rheumatoid arthritis (RA) is a systemic inflammatory disorder in which there is destruction of articular cartilage and bone. RA may be complicated by osteoporosis, but the cause of this generalised bone loss is not known. Bone resorption is carried out by osteoclasts which are formed from mononuclear precursors that circulate in the monocyte fraction. Objectives Our aims are to determine whether there is an increase in the number of circulating osteoclast precursors in RA patients relative to age/sex matched osteoarthritis (OA) controls. We also examined the sensitivity of these precursors to known factors required for osteoclastogenesis. Methods Peripheral blood mononuclear cells (PBMCs) from 10 RA patients and 10 age/sex matched OA controls were cultured on dentine slices and glass coverslips for up to 21 days in the presence of various concentrations of soluble RANKL (sRANKL) and M-CSF, or in the presence of RANKL-expressing UMR106 cells with various concentrations of M-CSF and 1,25(OH)2 vitamin D3. Cells were cultured with and without dexamethasone (Dex) at 10–8M. Results As assessed by expression of the osteoclast markers, TRAP and lacunar resorption, PBMC serial dilution studies showed no difference in the number of circulating osteoclast precursors in RA patients and OA controls. However, osteoclasts formed from PBMCs of RA patients were capable of substantially more resorption than osteoclasts formed in OA patients (p = 0.008). PBMCs from RA patients exhibited increased sensitivity to the osteoclastogenic effect of M-CSF when cultured with sRANKL (p = 0.004) or with UMR106 cells (p = 0.05). When cultured with UMR106 cells, an increase in sensitivity to 1,25(OH)2D3 (p = 0.02) was noted in RA patients compared to OA controls. PBMCs from RA patients also showed increased sensitivity to the effect of sRANKL. PBMCs from both RA (p = 0.001) and OA (p = 0.001) patients cultured in the presence of Dex exhibited significantly more lacunar resorption than cultures to which no Dex was added. Conclusion These findings suggest that the increase in generalised bone loss seen in RA results not from an increase in the absolute number of circulating osteoclast precursors but to an increase in the sensitivity of these precursors to local/systemic factors (i.e. M-CSF, RANKL, 1,25(OH)2D3 and corticosteroids) that influence osteoclast formation and bone resorbing activity. References Fujikawa Y, Quinn J, Sabikbar A, McGee JO, Athanasou NA. The human mononuclear osteoclast precursor circulates in the monocyte fraction. Endocrinology 1996;139:4058–60 Bertolini DR, Nedwin GE, Bringmann TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human TNF. Nature 1986;319;516–18