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Different cysteine proteinases involved in bone resorption and osteoclast formation

Brage, M; Abrahamson, Magnus LU ; Lindström, Veronica LU ; Grubb, Anders LU and Lerner, U H (2005) In Calcified Tissue International 76(6). p.439-447
Abstract
Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor... (More)
Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg(8), Leu(9), Val(10), and Trp(106) did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on catbepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cathepsin K, cystatins, osteoclasts, cysteine proteinases
in
Calcified Tissue International
volume
76
issue
6
pages
439 - 447
publisher
Springer
external identifiers
  • wos:000230309900007
  • pmid:15906014
  • scopus:23944524055
ISSN
1432-0827
DOI
10.1007/s00223-004-0043-y
language
English
LU publication?
yes
id
e026c5a1-f7d9-484d-b22b-88eab4405c42 (old id 233545)
date added to LUP
2007-08-08 13:55:19
date last changed
2017-05-21 04:30:16
@article{e026c5a1-f7d9-484d-b22b-88eab4405c42,
  abstract     = {Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg(8), Leu(9), Val(10), and Trp(106) did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on catbepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.},
  author       = {Brage, M and Abrahamson, Magnus and Lindström, Veronica and Grubb, Anders and Lerner, U H},
  issn         = {1432-0827},
  keyword      = {cathepsin K,cystatins,osteoclasts,cysteine proteinases},
  language     = {eng},
  number       = {6},
  pages        = {439--447},
  publisher    = {Springer},
  series       = {Calcified Tissue International},
  title        = {Different cysteine proteinases involved in bone resorption and osteoclast formation},
  url          = {http://dx.doi.org/10.1007/s00223-004-0043-y},
  volume       = {76},
  year         = {2005},
}