Osteoclastogenesis is decreased by cysteine proteinase inhibitors

被引:43
作者
Brage, M
Lie, A
Ransjö, M
Kasprzykowski, F
Kasprzykowska, R
Abrahamson, M
Grubb, A
Lerner, UH [1 ]
机构
[1] Umea Univ, Dept Oral & Cell Biol, S-90187 Umea, Sweden
[2] Univ Gdansk, Inst Chem, PL-80952 Gdansk, Poland
[3] Lund Univ, Dept Clin Chem, Lund, Sweden
关键词
osteoclasts; bone resorption; cysteine proteinases; cystatins;
D O I
10.1016/j.bone.2003.11.018
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)(2)-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP(+)) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for I-125-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of I-125-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:412 / 424
页数:13
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