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Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo. / Syberg, Susanne; Brandao-Burch, Andrea; Patel, Jessal J; Hajjawi, Mark; Arnett, Timothy R; Schwarz, Peter; Jorgensen, Niklas R; Orriss, Isabel R.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 27, No. 11, 11.2012, p. 2373-86.

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Syberg, Susanne ; Brandao-Burch, Andrea ; Patel, Jessal J ; Hajjawi, Mark ; Arnett, Timothy R ; Schwarz, Peter ; Jorgensen, Niklas R ; Orriss, Isabel R. / Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2012 ; Vol. 27, No. 11. pp. 2373-86.

Bibtex

@article{8de6d9f1f6d648ea914180fa3d1ed4e6,
title = "Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo",
abstract = "Clopidogrel (Plavix), a selective P2Y(12) receptor antagonist, is widely prescribed to reduce the risk of heart attack and stroke and acts via the inhibition of platelet aggregation. Accumulating evidence now suggests that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone, modulating both osteoblast and osteoclast function. In this study, we investigated the effects of clopidogrel treatment on (1) bone cell formation, differentiation, and activity in vitro; and (2) trabecular and cortical bone parameters in vivo. P2Y(12) receptor expression by osteoblasts and osteoclasts was confirmed using qPCR and Western blotting. Clopidogrel at 10 µM and 25 µM inhibited mineralized bone nodule formation by 50{\%} and >85{\%}, respectively. Clopidogrel slowed osteoblast proliferation with dose-dependent decreases in cell number (25{\%} to 40{\%}) evident in differentiating osteoblasts (day 7). A single dose of 10 to 25 µM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, ≥10 µM clopidogrel decreased alkaline phosphatase (ALP) activity by ≤70{\%} and collagen formation by 40{\%}, while increasing adipocyte formation. In osteoclasts, ≥1 µM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n = 10-12) were ovariectomized or sham treated and dosed orally with clopidogrel (1 mg/kg) or vehicle (NaCl) daily for 4 weeks. Dual-energy X-ray absorptiometry (DXA) analysis showed clopidogrel-treated animals had decreases of 2{\%} and 4{\%} in whole-body and femoral bone mineral density (BMD), respectively. Detailed analysis of trabecular and cortical bone using micro-computed tomography (microCT) showed decreased trabecular bone volume in the tibia (24{\%}) and femur (18{\%}) of clopidogrel-treated mice. Trabecular number was reduced 20{\%}, while trabecular separation was increased up to 15{\%}. Trabecular thickness and cortical bone parameters were unaffected. Combined, these findings indicate that long-term exposure of bone cells to clopidogrel in vivo could negatively impact bone health.",
keywords = "Alkaline Phosphatase/metabolism, Animals, Azo Compounds, Biomarkers/blood, Bone Density/drug effects, Bone Resorption/pathology, Bone and Bones/diagnostic imaging, Cell Count, Cell Survival/drug effects, Cells, Cultured, Clopidogrel, Collagen/metabolism, Cyclic AMP/metabolism, Gene Expression Regulation/drug effects, Intracellular Space/drug effects, Mice, Osteoblasts/drug effects, Osteoclasts/drug effects, Osteogenesis/drug effects, Purinergic P2Y Receptor Antagonists/pharmacology, Radiography, Receptors, Purinergic P2Y12/metabolism, Solubility, Staining and Labeling, Ticlopidine/analogs & derivatives",
author = "Susanne Syberg and Andrea Brandao-Burch and Patel, {Jessal J} and Mark Hajjawi and Arnett, {Timothy R} and Peter Schwarz and Jorgensen, {Niklas R} and Orriss, {Isabel R}",
note = "Copyright {\circledC} 2012 American Society for Bone and Mineral Research.",
year = "2012",
month = "11",
doi = "10.1002/jbmr.1690",
language = "English",
volume = "27",
pages = "2373--86",
journal = "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "11",

}

RIS

TY - JOUR

T1 - Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo

AU - Syberg, Susanne

AU - Brandao-Burch, Andrea

AU - Patel, Jessal J

AU - Hajjawi, Mark

AU - Arnett, Timothy R

AU - Schwarz, Peter

AU - Jorgensen, Niklas R

AU - Orriss, Isabel R

N1 - Copyright © 2012 American Society for Bone and Mineral Research.

PY - 2012/11

Y1 - 2012/11

N2 - Clopidogrel (Plavix), a selective P2Y(12) receptor antagonist, is widely prescribed to reduce the risk of heart attack and stroke and acts via the inhibition of platelet aggregation. Accumulating evidence now suggests that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone, modulating both osteoblast and osteoclast function. In this study, we investigated the effects of clopidogrel treatment on (1) bone cell formation, differentiation, and activity in vitro; and (2) trabecular and cortical bone parameters in vivo. P2Y(12) receptor expression by osteoblasts and osteoclasts was confirmed using qPCR and Western blotting. Clopidogrel at 10 µM and 25 µM inhibited mineralized bone nodule formation by 50% and >85%, respectively. Clopidogrel slowed osteoblast proliferation with dose-dependent decreases in cell number (25% to 40%) evident in differentiating osteoblasts (day 7). A single dose of 10 to 25 µM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, ≥10 µM clopidogrel decreased alkaline phosphatase (ALP) activity by ≤70% and collagen formation by 40%, while increasing adipocyte formation. In osteoclasts, ≥1 µM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n = 10-12) were ovariectomized or sham treated and dosed orally with clopidogrel (1 mg/kg) or vehicle (NaCl) daily for 4 weeks. Dual-energy X-ray absorptiometry (DXA) analysis showed clopidogrel-treated animals had decreases of 2% and 4% in whole-body and femoral bone mineral density (BMD), respectively. Detailed analysis of trabecular and cortical bone using micro-computed tomography (microCT) showed decreased trabecular bone volume in the tibia (24%) and femur (18%) of clopidogrel-treated mice. Trabecular number was reduced 20%, while trabecular separation was increased up to 15%. Trabecular thickness and cortical bone parameters were unaffected. Combined, these findings indicate that long-term exposure of bone cells to clopidogrel in vivo could negatively impact bone health.

AB - Clopidogrel (Plavix), a selective P2Y(12) receptor antagonist, is widely prescribed to reduce the risk of heart attack and stroke and acts via the inhibition of platelet aggregation. Accumulating evidence now suggests that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone, modulating both osteoblast and osteoclast function. In this study, we investigated the effects of clopidogrel treatment on (1) bone cell formation, differentiation, and activity in vitro; and (2) trabecular and cortical bone parameters in vivo. P2Y(12) receptor expression by osteoblasts and osteoclasts was confirmed using qPCR and Western blotting. Clopidogrel at 10 µM and 25 µM inhibited mineralized bone nodule formation by 50% and >85%, respectively. Clopidogrel slowed osteoblast proliferation with dose-dependent decreases in cell number (25% to 40%) evident in differentiating osteoblasts (day 7). A single dose of 10 to 25 µM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, ≥10 µM clopidogrel decreased alkaline phosphatase (ALP) activity by ≤70% and collagen formation by 40%, while increasing adipocyte formation. In osteoclasts, ≥1 µM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n = 10-12) were ovariectomized or sham treated and dosed orally with clopidogrel (1 mg/kg) or vehicle (NaCl) daily for 4 weeks. Dual-energy X-ray absorptiometry (DXA) analysis showed clopidogrel-treated animals had decreases of 2% and 4% in whole-body and femoral bone mineral density (BMD), respectively. Detailed analysis of trabecular and cortical bone using micro-computed tomography (microCT) showed decreased trabecular bone volume in the tibia (24%) and femur (18%) of clopidogrel-treated mice. Trabecular number was reduced 20%, while trabecular separation was increased up to 15%. Trabecular thickness and cortical bone parameters were unaffected. Combined, these findings indicate that long-term exposure of bone cells to clopidogrel in vivo could negatively impact bone health.

KW - Alkaline Phosphatase/metabolism

KW - Animals

KW - Azo Compounds

KW - Biomarkers/blood

KW - Bone Density/drug effects

KW - Bone Resorption/pathology

KW - Bone and Bones/diagnostic imaging

KW - Cell Count

KW - Cell Survival/drug effects

KW - Cells, Cultured

KW - Clopidogrel

KW - Collagen/metabolism

KW - Cyclic AMP/metabolism

KW - Gene Expression Regulation/drug effects

KW - Intracellular Space/drug effects

KW - Mice

KW - Osteoblasts/drug effects

KW - Osteoclasts/drug effects

KW - Osteogenesis/drug effects

KW - Purinergic P2Y Receptor Antagonists/pharmacology

KW - Radiography

KW - Receptors, Purinergic P2Y12/metabolism

KW - Solubility

KW - Staining and Labeling

KW - Ticlopidine/analogs & derivatives

U2 - 10.1002/jbmr.1690

DO - 10.1002/jbmr.1690

M3 - Article

C2 - 22714653

VL - 27

SP - 2373

EP - 2386

JO - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

SN - 0884-0431

IS - 11

ER -