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The C-Terminal Domain of Chondroadherin: A New Regulator of Osteoclast Motility Counteracting Bone Loss

Capulli, Mattia; Olstad, Ole K.; Önnerfjord, Patrik LU ; Tillgren, Viveka LU ; Muraca, Maurizio; Gautvik, Kaare M.; Heinegård, Dick LU ; Rucci, Nadia and Teti, Anna (2014) In Journal of Bone and Mineral Research 29(8). p.1833-1846
Abstract
Chondroadherin (CHAD) is a leucine-rich protein promoting cell attachment through binding to integrin alpha(2)beta(1) and syndecans. We observed that CHAD mRNA and protein were lower in bone biopsies of 50-year-old to 65-year-old osteoporotic women and in bone samples of ovariectomized mice versus gender/age-matched controls, suggesting a role in bone metabolism. By the means of an internal cyclic peptide (cyclicCHAD), we observed that its integrin binding sequence impaired preosteoclast migration through a nitric oxide synthase 2-dependent mechanism, decreasing osteoclastogenesis and bone resorption in a concentration-dependent fashion, whereas it had no effect on osteoblasts. Consistently, cyclicCHAD reduced transcription of two nitric... (More)
Chondroadherin (CHAD) is a leucine-rich protein promoting cell attachment through binding to integrin alpha(2)beta(1) and syndecans. We observed that CHAD mRNA and protein were lower in bone biopsies of 50-year-old to 65-year-old osteoporotic women and in bone samples of ovariectomized mice versus gender/age-matched controls, suggesting a role in bone metabolism. By the means of an internal cyclic peptide (cyclicCHAD), we observed that its integrin binding sequence impaired preosteoclast migration through a nitric oxide synthase 2-dependent mechanism, decreasing osteoclastogenesis and bone resorption in a concentration-dependent fashion, whereas it had no effect on osteoblasts. Consistently, cyclicCHAD reduced transcription of two nitric oxide downstream genes, migfilin and vasp, involved in cell motility. Furthermore, the nitric oxide donor, S-nitroso-N-acetyl-D, L-penicillamine, stimulated preosteoclast migration and prevented the inhibitory effect of cyclicCHAD. Conversely, the nitric oxide synthase 2 (NOS2) inhibitor, N5-(1-iminoethyl)-l-ornithine, decreased both preosteoclast migration and differentiation, confirming a role of the nitric oxide pathway in the mechanism of action triggered by cyclicCHAD. In vivo, administration of cyclicCHAD was well tolerated and increased bone volume in healthy mice, with no adverse effect. In ovariectomized mice cyclicCHAD improved bone mass by both a preventive and a curative treatment protocol, with an effect in line with that of the bisphosphonate alendronate, that was mimicked by the NOS2 inhibitor [L-N6-(1-Iminoethyl)-lysine. 2 dihydrochloride]. In both mouse models, cyclicCHAD reduced osteoclast and bone resorption without affecting osteoblast parameters and bone formation. In conclusion, CHAD is a novel regulator of bone metabolism that, through its integrin binding domain, inhibits preosteoclast motility and bone resorption, with a potential translational impact for the treatment of osteoporosis. (C) 2014 American Society for Bone and Mineral Research. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CHONDROADHERIN, OSTEOCLASTS, OSTEOPOROSIS
in
Journal of Bone and Mineral Research
volume
29
issue
8
pages
1833 - 1846
publisher
AMBMR
external identifiers
  • wos:000340243900016
  • scopus:84904623430
ISSN
1523-4681
DOI
10.1002/jbmr.2206
language
English
LU publication?
yes
id
3aa00aae-5e1d-4871-988a-d566e7d6c7a4 (old id 4659593)
date added to LUP
2014-10-01 07:23:19
date last changed
2017-10-22 03:12:35
@article{3aa00aae-5e1d-4871-988a-d566e7d6c7a4,
  abstract     = {Chondroadherin (CHAD) is a leucine-rich protein promoting cell attachment through binding to integrin alpha(2)beta(1) and syndecans. We observed that CHAD mRNA and protein were lower in bone biopsies of 50-year-old to 65-year-old osteoporotic women and in bone samples of ovariectomized mice versus gender/age-matched controls, suggesting a role in bone metabolism. By the means of an internal cyclic peptide (cyclicCHAD), we observed that its integrin binding sequence impaired preosteoclast migration through a nitric oxide synthase 2-dependent mechanism, decreasing osteoclastogenesis and bone resorption in a concentration-dependent fashion, whereas it had no effect on osteoblasts. Consistently, cyclicCHAD reduced transcription of two nitric oxide downstream genes, migfilin and vasp, involved in cell motility. Furthermore, the nitric oxide donor, S-nitroso-N-acetyl-D, L-penicillamine, stimulated preosteoclast migration and prevented the inhibitory effect of cyclicCHAD. Conversely, the nitric oxide synthase 2 (NOS2) inhibitor, N5-(1-iminoethyl)-l-ornithine, decreased both preosteoclast migration and differentiation, confirming a role of the nitric oxide pathway in the mechanism of action triggered by cyclicCHAD. In vivo, administration of cyclicCHAD was well tolerated and increased bone volume in healthy mice, with no adverse effect. In ovariectomized mice cyclicCHAD improved bone mass by both a preventive and a curative treatment protocol, with an effect in line with that of the bisphosphonate alendronate, that was mimicked by the NOS2 inhibitor [L-N6-(1-Iminoethyl)-lysine. 2 dihydrochloride]. In both mouse models, cyclicCHAD reduced osteoclast and bone resorption without affecting osteoblast parameters and bone formation. In conclusion, CHAD is a novel regulator of bone metabolism that, through its integrin binding domain, inhibits preosteoclast motility and bone resorption, with a potential translational impact for the treatment of osteoporosis. (C) 2014 American Society for Bone and Mineral Research.},
  author       = {Capulli, Mattia and Olstad, Ole K. and Önnerfjord, Patrik and Tillgren, Viveka and Muraca, Maurizio and Gautvik, Kaare M. and Heinegård, Dick and Rucci, Nadia and Teti, Anna},
  issn         = {1523-4681},
  keyword      = {CHONDROADHERIN,OSTEOCLASTS,OSTEOPOROSIS},
  language     = {eng},
  number       = {8},
  pages        = {1833--1846},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {The C-Terminal Domain of Chondroadherin: A New Regulator of Osteoclast Motility Counteracting Bone Loss},
  url          = {http://dx.doi.org/10.1002/jbmr.2206},
  volume       = {29},
  year         = {2014},
}