The effects of anti-inflammatory and anti-rheumatic drugs, immunomodulators on bone resorption.
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Rheumatoid arthritis (RA) is a systemic and chronic disorder involving joint damage. Recent studies have demonstrated changes in bone metabolism in patients with RA. Therefore, the aim of this study was to investigate the effects of some therapeutic drugs for RA on bone resorption<I>in vitro</I>. The bone resorption was studied by measuring of calcium contents in medium released from mouse calvaria in tissue culture. Parathyroid hormone (PTH) and recombinant human interleukin 1β (rhIL-1β), bone resorting factor, was used in this experiment. The calcium contents in the medium with mouse calvaria was significantly increased by the presence of PTH (10-100nM) and rhIL-1β (3 -30U/ml) in a dose dependent manner. The increase in the medium calcium contents induced by PTH was inhibited by the coexistence of cyclosporin (l0μM) and methotrexate (1-10μM) whereas was not blocked by the presence of 10μM sulfasalazine, aurothioglucose, indomethacin, diclofenac Na, ketoprofen and bucillamine. However, rhIL-1β stimulating bone resorption was inhibited completely by indomethacin, diclofenac Na, ketoprofen and cyclosporin at 10μM. However sulfasalazine, aurothioglucose and methotrexate had not effect on rhIL-1β stimulating calcium release. At 10μM, bucillamine tend to enhance the calcium release from mouse calvaria by rh1L-1β. Furthermore, the calcium release by PTH and rhIL-1β was strongly prevented by bafilomycin A<SUB>1</SUB> in doses between 1 nM and 10 nM.<BR>The effect of therapeutic drugs for RA was investigated in cloned osteoblast-like osteosarcoma cell (Saos-2) . Cells were cultured for 1 day at 37°C in a CO<SUB>2</SUB>incubator in plastic dishes containing McCoy's 5 A medium supplemented with 10% fetal bovine serum (FCS) . After the cultures, the medium exchanged for FCS-free medium containing upper drugs and the cells were cultured further for 72h. Alkaline phosphatase (ALP) activity and DNA content in Saos-2 cells was significantly inhibited by cyclosporin (10μM) . Also, only DNA content in Saos-2 cells was significantly inhibited by methotrexate (10μM) . However, diclofenac Na, indomethacin, ketoprofen, bucillamine, sulfasalazine and aurothioglucose at the concentration of 10μM did not effect on ALP activity and DNA contents in the cells.<BR>These results indicated that NSAIDs had an inhibitory effects of bone resorption by rhIL-1β rather than PTH, but DMARDs had not directly inhibition by them, and, immunosuppresser, cyclosporine and methotrexate, had an inhibitory effects of bone resorption by PTH and/or rhIL-1β, but these two drugs also prevented osteoblastic function. From a clinical standpoint, the development of inhibitory drugs for bone resorption blocked or reduced the rate of progression of bone damage in RA without the inhibitory effect of osteoblast may be important.
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