Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification

Belinda A. Di Bartolo, Michael Schoppet, Muhammad Z. Mattar, Tilman D. Rachner, Catherine M. Shanahan, Mary M. Kavurma

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Aims Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG -/- mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R. Methods and results Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calciums induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue. Conclusion We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.

LanguageEnglish
Pages537-545
Number of pages9
JournalCardiovascular Research
Volume91
Issue number3
DOIs
Publication statusPublished - 1 Aug 2011

Keywords

  • Calcium
  • IGF1R
  • Osteoprotegerin
  • Smooth muscle cell
  • Vascular calcification

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Di Bartolo, B. A., Schoppet, M., Mattar, M. Z., Rachner, T. D., Shanahan, C. M., & Kavurma, M. M. (2011). Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. Cardiovascular Research, 91(3), 537-545. https://doi.org/10.1093/cvr/cvr084
Di Bartolo, Belinda A. ; Schoppet, Michael ; Mattar, Muhammad Z. ; Rachner, Tilman D. ; Shanahan, Catherine M. ; Kavurma, Mary M. / Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. In: Cardiovascular Research. 2011 ; Vol. 91, No. 3. pp. 537-545.
@article{e67a9303d0cf4c8eb3028b66efcb4522,
title = "Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification",
abstract = "Aims Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG -/- mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R. Methods and results Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calciums induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue. Conclusion We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.",
keywords = "Calcium, IGF1R, Osteoprotegerin, Smooth muscle cell, Vascular calcification",
author = "{Di Bartolo}, {Belinda A.} and Michael Schoppet and Mattar, {Muhammad Z.} and Rachner, {Tilman D.} and Shanahan, {Catherine M.} and Kavurma, {Mary M.}",
year = "2011",
month = "8",
day = "1",
doi = "10.1093/cvr/cvr084",
language = "English",
volume = "91",
pages = "537--545",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "3",

}

Di Bartolo, BA, Schoppet, M, Mattar, MZ, Rachner, TD, Shanahan, CM & Kavurma, MM 2011, 'Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification', Cardiovascular Research, vol. 91, no. 3, pp. 537-545. https://doi.org/10.1093/cvr/cvr084

Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. / Di Bartolo, Belinda A.; Schoppet, Michael; Mattar, Muhammad Z.; Rachner, Tilman D.; Shanahan, Catherine M.; Kavurma, Mary M.

In: Cardiovascular Research, Vol. 91, No. 3, 01.08.2011, p. 537-545.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification

AU - Di Bartolo, Belinda A.

AU - Schoppet, Michael

AU - Mattar, Muhammad Z.

AU - Rachner, Tilman D.

AU - Shanahan, Catherine M.

AU - Kavurma, Mary M.

PY - 2011/8/1

Y1 - 2011/8/1

N2 - Aims Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG -/- mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R. Methods and results Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calciums induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue. Conclusion We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.

AB - Aims Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG -/- mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R. Methods and results Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calciums induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue. Conclusion We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.

KW - Calcium

KW - IGF1R

KW - Osteoprotegerin

KW - Smooth muscle cell

KW - Vascular calcification

UR - http://www.scopus.com/inward/record.url?scp=79959887174&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvr084

DO - 10.1093/cvr/cvr084

M3 - Article

VL - 91

SP - 537

EP - 545

JO - Cardiovascular Research

T2 - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 3

ER -

Di Bartolo BA, Schoppet M, Mattar MZ, Rachner TD, Shanahan CM, Kavurma MM. Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification. Cardiovascular Research. 2011 Aug 1;91(3):537-545. https://doi.org/10.1093/cvr/cvr084