The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

Xinming Su; Desiree H Floyd; Alun Hughes; Jingyu Xiang; Jochen G Schneider; Ozge Uluckan; Emanuela Heller; Hongju Deng; Wei Zou; Clarissa S Craft; Kaiming Wu; Angela C Hirbe; Dorota Grabowska; Mark C Eagleton; Sarah Townsley; Lynne Collins; David Piwnica-Worms; Thomas H Steinberg; Deborah V Novack; Pamela B Conley; Michelle A Hurchla; Michael Rogers; Katherine N Weilbaecher

doi:10.1172/JCI38576

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

Xinming Su, Desiree H Floyd, Alun Hughes, Jingyu Xiang, Jochen G Schneider, Ozge Uluckan, Emanuela Heller, Hongju Deng, Wei Zou, Clarissa S Craft, Kaiming Wu, Angela C Hirbe, Dorota Grabowska, Mark C Eagleton, Sarah Townsley, Lynne Collins, David Piwnica-Worms, Thomas H Steinberg, Deborah V Novack, Pamela B ConleyMichelle A Hurchla, Michael Rogers, Katherine N Weilbaecher

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.

Original language	English
Pages (from-to)	3579-92
Number of pages	14
Journal	The Journal of Clinical Investigation
Volume	122
Issue number	10
DOIs	https://doi.org/10.1172/JCI38576
Publication status	Published - Oct 2012

Keywords

Adenosine Diphosphate/physiology
Animals
Arthritis, Experimental/complications
Bone Neoplasms/complications
Bone Remodeling/drug effects
Bone Resorption/physiopathology
Carcinoma/complications
Cell Adhesion/drug effects
Cells, Cultured/drug effects
Clopidogrel
Enzyme Activation/drug effects
Female
Mammary Neoplasms, Experimental/pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoclasts/physiology
Osteoporosis/etiology
Ovariectomy
Phosphatidylinositol 3-Kinases/physiology
Phosphoinositide-3 Kinase Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex/drug effects
Purinergic P2Y Receptor Antagonists/pharmacology
Receptors, Purinergic P2Y12/deficiency
Specific Pathogen-Free Organisms
Ticlopidine/analogs & derivatives
rap1 GTP-Binding Proteins/drug effects

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10.1172/JCI38576

Cite this

Su, X., Floyd, D. H., Hughes, A., Xiang, J., Schneider, J. G., Uluckan, O., Heller, E., Deng, H., Zou, W., Craft, C. S., Wu, K., Hirbe, A. C., Grabowska, D., Eagleton, M. C., Townsley, S., Collins, L., Piwnica-Worms, D., Steinberg, T. H., Novack, D. V., ... Weilbaecher, K. N. (2012). The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. The Journal of Clinical Investigation, 122(10), 3579-92. https://doi.org/10.1172/JCI38576

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title = "The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling",

abstract = "The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.",

keywords = "Adenosine Diphosphate/physiology, Animals, Arthritis, Experimental/complications, Bone Neoplasms/complications, Bone Remodeling/drug effects, Bone Resorption/physiopathology, Carcinoma/complications, Cell Adhesion/drug effects, Cells, Cultured/drug effects, Clopidogrel, Enzyme Activation/drug effects, Female, Mammary Neoplasms, Experimental/pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoclasts/physiology, Osteoporosis/etiology, Ovariectomy, Phosphatidylinositol 3-Kinases/physiology, Phosphoinositide-3 Kinase Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex/drug effects, Purinergic P2Y Receptor Antagonists/pharmacology, Receptors, Purinergic P2Y12/deficiency, Specific Pathogen-Free Organisms, Ticlopidine/analogs & derivatives, rap1 GTP-Binding Proteins/drug effects",

author = "Xinming Su and Floyd, {Desiree H} and Alun Hughes and Jingyu Xiang and Schneider, {Jochen G} and Ozge Uluckan and Emanuela Heller and Hongju Deng and Wei Zou and Craft, {Clarissa S} and Kaiming Wu and Hirbe, {Angela C} and Dorota Grabowska and Eagleton, {Mark C} and Sarah Townsley and Lynne Collins and David Piwnica-Worms and Steinberg, {Thomas H} and Novack, {Deborah V} and Conley, {Pamela B} and Hurchla, {Michelle A} and Michael Rogers and Weilbaecher, {Katherine N}",

year = "2012",

month = oct,

doi = "10.1172/JCI38576",

language = "English",

volume = "122",

pages = "3579--92",

journal = "The Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "10",

}

Su, X, Floyd, DH, Hughes, A, Xiang, J, Schneider, JG, Uluckan, O, Heller, E, Deng, H, Zou, W, Craft, CS, Wu, K, Hirbe, AC, Grabowska, D, Eagleton, MC, Townsley, S, Collins, L, Piwnica-Worms, D, Steinberg, TH, Novack, DV, Conley, PB, Hurchla, MA, Rogers, M & Weilbaecher, KN 2012, 'The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling', The Journal of Clinical Investigation, vol. 122, no. 10, pp. 3579-92. https://doi.org/10.1172/JCI38576

TY - JOUR

T1 - The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

AU - Su, Xinming

AU - Floyd, Desiree H

AU - Hughes, Alun

AU - Xiang, Jingyu

AU - Schneider, Jochen G

AU - Uluckan, Ozge

AU - Heller, Emanuela

AU - Deng, Hongju

AU - Zou, Wei

AU - Craft, Clarissa S

AU - Wu, Kaiming

AU - Hirbe, Angela C

AU - Grabowska, Dorota

AU - Eagleton, Mark C

AU - Townsley, Sarah

AU - Collins, Lynne

AU - Piwnica-Worms, David

AU - Steinberg, Thomas H

AU - Novack, Deborah V

AU - Conley, Pamela B

AU - Hurchla, Michelle A

AU - Rogers, Michael

AU - Weilbaecher, Katherine N

PY - 2012/10

Y1 - 2012/10

N2 - The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.

AB - The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.

KW - Adenosine Diphosphate/physiology

KW - Animals

KW - Arthritis, Experimental/complications

KW - Bone Neoplasms/complications

KW - Bone Remodeling/drug effects

KW - Bone Resorption/physiopathology

KW - Carcinoma/complications

KW - Cell Adhesion/drug effects

KW - Cells, Cultured/drug effects

KW - Clopidogrel

KW - Enzyme Activation/drug effects

KW - Female

KW - Mammary Neoplasms, Experimental/pathology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Osteoclasts/physiology

KW - Osteoporosis/etiology

KW - Ovariectomy

KW - Phosphatidylinositol 3-Kinases/physiology

KW - Phosphoinositide-3 Kinase Inhibitors

KW - Platelet Glycoprotein GPIIb-IIIa Complex/drug effects

KW - Purinergic P2Y Receptor Antagonists/pharmacology

KW - Receptors, Purinergic P2Y12/deficiency

KW - Specific Pathogen-Free Organisms

KW - Ticlopidine/analogs & derivatives

KW - rap1 GTP-Binding Proteins/drug effects

U2 - 10.1172/JCI38576

DO - 10.1172/JCI38576

M3 - Article

C2 - 22996695

SN - 0021-9738

VL - 122

SP - 3579

EP - 3592

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

IS - 10

ER -

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

Abstract

Keywords

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