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Title: Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

Abstract

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRII ocy-/-), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility. Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.

Authors:
 [1];  [2];  [3];  [2];  [2];  [1];  [4];  [4];  [5];  [6];  [7];  [1];  [8];  [6];  [5];  [2]
  1. Univ. of California, San Francisco, CA (United States)
  2. Univ. of California, San Francisco, CA (United States); UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, CA (United States)
  3. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  5. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
  7. California Pacific Medical Center Research Institute, San Francisco, CA (United States)
  8. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1410487
Alternate Identifier(s):
OSTI ID: 1420129
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 21; Journal Issue: 9; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; osteocyte; TGF-β; bone quality; perilacunar/canalicular remodeling; bone fragility

Citation Formats

Dole, Neha S., Mazur, Courtney M., Acevedo, Claire, Lopez, Justin P., Monteiro, David A., Fowler, Tristan W., Gludovatz, Bernd, Walsh, Flynn, Regan, Jenna N., Messina, Sara, Evans, Daniel S., Lang, Thomas F., Zhang, Bin, Ritchie, Robert O., Mohammad, Khalid S., and Alliston, Tamara. Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling. United States: N. p., 2017. Web. doi:10.1016/j.celrep.2017.10.115.
Dole, Neha S., Mazur, Courtney M., Acevedo, Claire, Lopez, Justin P., Monteiro, David A., Fowler, Tristan W., Gludovatz, Bernd, Walsh, Flynn, Regan, Jenna N., Messina, Sara, Evans, Daniel S., Lang, Thomas F., Zhang, Bin, Ritchie, Robert O., Mohammad, Khalid S., & Alliston, Tamara. Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling. United States. doi:10.1016/j.celrep.2017.10.115.
Dole, Neha S., Mazur, Courtney M., Acevedo, Claire, Lopez, Justin P., Monteiro, David A., Fowler, Tristan W., Gludovatz, Bernd, Walsh, Flynn, Regan, Jenna N., Messina, Sara, Evans, Daniel S., Lang, Thomas F., Zhang, Bin, Ritchie, Robert O., Mohammad, Khalid S., and Alliston, Tamara. Tue . "Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling". United States. doi:10.1016/j.celrep.2017.10.115.
@article{osti_1410487,
title = {Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling},
author = {Dole, Neha S. and Mazur, Courtney M. and Acevedo, Claire and Lopez, Justin P. and Monteiro, David A. and Fowler, Tristan W. and Gludovatz, Bernd and Walsh, Flynn and Regan, Jenna N. and Messina, Sara and Evans, Daniel S. and Lang, Thomas F. and Zhang, Bin and Ritchie, Robert O. and Mohammad, Khalid S. and Alliston, Tamara},
abstractNote = {Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy-/-), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility. Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.},
doi = {10.1016/j.celrep.2017.10.115},
journal = {Cell Reports},
number = 9,
volume = 21,
place = {United States},
year = {Tue Nov 28 00:00:00 EST 2017},
month = {Tue Nov 28 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.celrep.2017.10.115

Citation Metrics:
Cited by: 1 work
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