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Proline/arginine-rich end leucine-rich repeat protein N-terminus is a novel osteoclast antagonist that counteracts bone loss

Rucci, Nadia ; Capulli, Mattia ; Ventura, Luca ; Angelucci, Adriano ; Peruzzi, Barbara ; Tillgren, Viveka LU ; Muraca, Maurizio ; Heinegård, Dick LU and Teti, Anna (2013) In Journal of Bone and Mineral Research 28(9). p.1912-1924
Abstract
(PRELP)-P-hbd is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). (PRELP)-P-hbd inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-B transcription factor activity. In this work, we hypothesized that (PRELP)-P-hbd could have a pharmacological relevance, counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an... (More)
(PRELP)-P-hbd is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). (PRELP)-P-hbd inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-B transcription factor activity. In this work, we hypothesized that (PRELP)-P-hbd could have a pharmacological relevance, counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an acute increase of osteoclast formation, the peptide consistently antagonized osteoclastogenesis and prevented the increase of the serum levels of the osteoclast-specific marker tartrate-resistant acid phosphatase. In ovariectomized mice, in which osteoclast activity was chronically enhanced by estrogen deficiency, (PRELP)-P-hbd counteracted exacerbated osteoclast activity and bone loss. In mice carrying osteolytic bone metastases, in which osteoclastogenesis and bone resorption were enhanced by tumor cell-derived factors, (PRELP)-P-hbd reduced the incidence of osteolytic lesions, both preventively and curatively, with mechanisms involving impaired tumor cell homing to bone and tumor growth in the bone microenvironment. Interestingly, in tumor-bearing mice, (PRELP)-P-hbd also inhibited breast tumor growth in orthotopic sites and development of metastatic disease in visceral organs, reducing cachexia and improving survival especially when administered preventively. (PRELP)-P-hbd was retained in the tumor tissue and appeared to affect tumor growth by interacting with the microenvironment rather than by directly affecting the tumor cells. Because safety studies and high-dose treatments revealed no adverse effects, (PRELP)-P-hbd could be employed as a novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact. (C) 2013 American Society for Bone and Mineral Research. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
(PRELP)-P-hbd, BONE LOSS, OSTEOPOROSIS, BREAST CANCER METASTASIS
in
Journal of Bone and Mineral Research
volume
28
issue
9
pages
1912 - 1924
publisher
Wiley-Blackwell
external identifiers
  • wos:000323204300007
  • scopus:84882578710
  • pmid:23559035
ISSN
1523-4681
DOI
10.1002/jbmr.1951
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Connective Tissue Biology (013230151)
id
820d25e3-a89a-400d-979a-72772b13dd42 (old id 4027166)
date added to LUP
2016-04-01 10:21:50
date last changed
2022-03-27 07:37:52
@article{820d25e3-a89a-400d-979a-72772b13dd42,
  abstract     = {{(PRELP)-P-hbd is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). (PRELP)-P-hbd inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-B transcription factor activity. In this work, we hypothesized that (PRELP)-P-hbd could have a pharmacological relevance, counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an acute increase of osteoclast formation, the peptide consistently antagonized osteoclastogenesis and prevented the increase of the serum levels of the osteoclast-specific marker tartrate-resistant acid phosphatase. In ovariectomized mice, in which osteoclast activity was chronically enhanced by estrogen deficiency, (PRELP)-P-hbd counteracted exacerbated osteoclast activity and bone loss. In mice carrying osteolytic bone metastases, in which osteoclastogenesis and bone resorption were enhanced by tumor cell-derived factors, (PRELP)-P-hbd reduced the incidence of osteolytic lesions, both preventively and curatively, with mechanisms involving impaired tumor cell homing to bone and tumor growth in the bone microenvironment. Interestingly, in tumor-bearing mice, (PRELP)-P-hbd also inhibited breast tumor growth in orthotopic sites and development of metastatic disease in visceral organs, reducing cachexia and improving survival especially when administered preventively. (PRELP)-P-hbd was retained in the tumor tissue and appeared to affect tumor growth by interacting with the microenvironment rather than by directly affecting the tumor cells. Because safety studies and high-dose treatments revealed no adverse effects, (PRELP)-P-hbd could be employed as a novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact. (C) 2013 American Society for Bone and Mineral Research.}},
  author       = {{Rucci, Nadia and Capulli, Mattia and Ventura, Luca and Angelucci, Adriano and Peruzzi, Barbara and Tillgren, Viveka and Muraca, Maurizio and Heinegård, Dick and Teti, Anna}},
  issn         = {{1523-4681}},
  keywords     = {{(PRELP)-P-hbd; BONE LOSS; OSTEOPOROSIS; BREAST CANCER METASTASIS}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1912--1924}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Bone and Mineral Research}},
  title        = {{Proline/arginine-rich end leucine-rich repeat protein N-terminus is a novel osteoclast antagonist that counteracts bone loss}},
  url          = {{http://dx.doi.org/10.1002/jbmr.1951}},
  doi          = {{10.1002/jbmr.1951}},
  volume       = {{28}},
  year         = {{2013}},
}