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Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling

Stralberg, Fredrik; Henning, Petra; Gjertsson, Inger; Kindlund, Bert; Souza, Pedro P. C.; Persson, Emma; Abrahamson, Magnus LU ; Kasprzykowski, Franciszek; Grubb, Anders LU and Lerner, Ulf H. (2013) In FASEB Journal 27(7). p.2687-2701
Abstract
The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 M. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 M), and E-64 (IC50 3 M), also inhibited... (More)
The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 M. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 M), and E-64 (IC50 3 M), also inhibited osteoclast formation in RANKL-stimulated macrophages. In addition, cystatin C, Z-RLVG-CHN2, and E-64 inhibited osteoclastic differentiation of RANKL-stimulated CD14(+) human monocytes. The effect by cystatin C on differentiation of bone marrow macrophages was exerted at an early stage after RANKL stimulation and was associated with early (4 h) inhibition of c-Fos expression and decreased protein and nuclear translocation of c-Fos. Subsequently, p52, p65, IB, and Nfatc1 mRNA were decreased. Cystatin C was internalized in osteoclast progenitors, a process requiring RANKL stimulation. These data show that cystatin C inhibits osteoclast differentiation and formation by interfering intracellularly with signaling pathways downstream RANK. Stralberg, F., Henning, P., Gjertsson, I., Kindlund, B-., Souza, P. P. C., Persson, E., Abrahamson, M., Kasprzykowski, F., Grubb, A., Lerner, U. H. Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cystatin C, osteoclasts, Nfatc1, c-Fos
in
FASEB Journal
volume
27
issue
7
pages
2687 - 2701
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • wos:000328841000018
  • scopus:84879637850
ISSN
1530-6860
DOI
10.1096/fj.12-211748
language
English
LU publication?
yes
id
f1620448-5d62-4167-897b-8cbc8d9748ad (old id 4261743)
date added to LUP
2014-02-10 12:15:34
date last changed
2019-06-30 03:57:29
@article{f1620448-5d62-4167-897b-8cbc8d9748ad,
  abstract     = {The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 M. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 M), and E-64 (IC50 3 M), also inhibited osteoclast formation in RANKL-stimulated macrophages. In addition, cystatin C, Z-RLVG-CHN2, and E-64 inhibited osteoclastic differentiation of RANKL-stimulated CD14(+) human monocytes. The effect by cystatin C on differentiation of bone marrow macrophages was exerted at an early stage after RANKL stimulation and was associated with early (4 h) inhibition of c-Fos expression and decreased protein and nuclear translocation of c-Fos. Subsequently, p52, p65, IB, and Nfatc1 mRNA were decreased. Cystatin C was internalized in osteoclast progenitors, a process requiring RANKL stimulation. These data show that cystatin C inhibits osteoclast differentiation and formation by interfering intracellularly with signaling pathways downstream RANK. Stralberg, F., Henning, P., Gjertsson, I., Kindlund, B-., Souza, P. P. C., Persson, E., Abrahamson, M., Kasprzykowski, F., Grubb, A., Lerner, U. H. Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling.},
  author       = {Stralberg, Fredrik and Henning, Petra and Gjertsson, Inger and Kindlund, Bert and Souza, Pedro P. C. and Persson, Emma and Abrahamson, Magnus and Kasprzykowski, Franciszek and Grubb, Anders and Lerner, Ulf H.},
  issn         = {1530-6860},
  keyword      = {cystatin C,osteoclasts,Nfatc1,c-Fos},
  language     = {eng},
  number       = {7},
  pages        = {2687--2701},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB Journal},
  title        = {Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling},
  url          = {http://dx.doi.org/10.1096/fj.12-211748},
  volume       = {27},
  year         = {2013},
}