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Heterozygous human tumour necrosis factor α transgenic (hTNFαtg) mice and wild-type littermates were intravenously injected with 0.75 mg/kg bortezomib or phosphate buffered saline twice a week. Mice were weekly assessed for clinical signs of arthritis. After 6 weeks of treatment the mice were analysed for synovial inflammation, cartilage damage, bone erosions and systemic bone turnover. Osteoclast precursors from hTNFαtg mice were obtained from bone marrow and treated with different concentrations of bortezomib. In addition, osteoclasts were analysed by western blot analysis and real-time PCR in more detail.
Bortezomib-treated hTNFαtg mice showed moderately increased inflammatory activity and dramatically enhanced bone erosions correlating with a significant increase of synovial osteoclasts. Interestingly, bortezomib did not alter systemic bone turnover in TNFαtg or in wild-type mice. In vitro, therapeutically relevant concentrations of bortezomib resulted in an increased differentiation of monocytes into osteoclasts. Consequently, bortezomib-treated osteoclasts caused resorption pits of higher extent than untreated osteoclasts. Molecularly, bortezomib increased the expression of TRAF6, c-fos and NFAT-c1.
In TNF-mediated bone destruction, bortezomib increases synovial osteoclastogenesis and bone destruction. Bortezomib might therefore have a direct osteodestructive effect via stimulation of osteoclastogenesis as well as a more indirect osteoprotective effect—for instance, by killing myeloma cells.
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