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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 (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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1410487
Alternate Identifier(s):
OSTI ID: 1420129
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Name: Cell Reports Journal Volume: 21 Journal Issue: 9; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
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. Netherlands: 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. Netherlands. 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. Wed . "Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling". Netherlands. 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 = {Netherlands},
year = {2017},
month = {11}
}

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

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Cited by: 5 works
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Works referencing / citing this record:

Investigating Osteocytic Perilacunar/Canalicular Remodeling
journal, June 2019

  • Yee, Cristal S.; Schurman, Charles A.; White, Carter R.
  • Current Osteoporosis Reports, Vol. 17, Issue 4
  • DOI: 10.1007/s11914-019-00514-0

TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
journal, June 2019


Cathepsin K–deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression
journal, June 2019

  • Lotinun, Sutada; Ishihara, Yoshihito; Nagano, Kenichi
  • Journal of Clinical Investigation, Vol. 129, Issue 8
  • DOI: 10.1172/jci122936

Investigating Osteocytic Perilacunar/Canalicular Remodeling
journal, June 2019

  • Yee, Cristal S.; Schurman, Charles A.; White, Carter R.
  • Current Osteoporosis Reports, Vol. 17, Issue 4
  • DOI: 10.1007/s11914-019-00514-0

TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
journal, June 2019


Cathepsin K–deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression
journal, June 2019

  • Lotinun, Sutada; Ishihara, Yoshihito; Nagano, Kenichi
  • Journal of Clinical Investigation, Vol. 129, Issue 8
  • DOI: 10.1172/jci122936

Different effects of soybean isoflavone genistein on transforming growth factor levels during orthodontic tooth movement among young and old rabbits
journal, January 2019