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Title: The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts

Abstract

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss related inflammatory conditions.

Authors:
 [1];  [1];  [2]; ORCiD logo [3];  [4];  [3];  [1]
  1. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine, Dept. of Pathology and Lab. Medicine
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine, Dept. of Pathology and Lab. Medicine; Osaka Univ., Suita (Japan). WPI-Immunology Frontier Research Center
  3. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Biology. School of Arts and Sciences, Dept. of Computer and Information Science
  4. Kyungpook National Univ., Daegu (Korea, Republic of). School of Dentistry, Dept. of Oral Pathology
Publication Date:
Research Org.:
Krell Inst., Ames, IA (United States)
Sponsoring Org.:
USDOE; Molecular Biology Society of Japan: National Institutes of Health (NIH)
OSTI Identifier:
1366532
Grant/Contract Number:
FG02-97ER25308; AR067726
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Kim, Hyunsoo, Walsh, Matthew C., Takegahara, Noriko, Middleton, Sarah A., Shin, Hong-In, Kim, Junhyong, and Choi, Yongwon. The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. United States: N. p., 2017. Web. doi:10.1038/s41598-017-00139-2.
Kim, Hyunsoo, Walsh, Matthew C., Takegahara, Noriko, Middleton, Sarah A., Shin, Hong-In, Kim, Junhyong, & Choi, Yongwon. The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts. United States. doi:10.1038/s41598-017-00139-2.
Kim, Hyunsoo, Walsh, Matthew C., Takegahara, Noriko, Middleton, Sarah A., Shin, Hong-In, Kim, Junhyong, and Choi, Yongwon. Wed . "The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts". United States. doi:10.1038/s41598-017-00139-2. https://www.osti.gov/servlets/purl/1366532.
@article{osti_1366532,
title = {The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts},
author = {Kim, Hyunsoo and Walsh, Matthew C. and Takegahara, Noriko and Middleton, Sarah A. and Shin, Hong-In and Kim, Junhyong and Choi, Yongwon},
abstractNote = {Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss related inflammatory conditions.},
doi = {10.1038/s41598-017-00139-2},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {Wed Mar 15 00:00:00 EDT 2017},
month = {Wed Mar 15 00:00:00 EDT 2017}
}

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