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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
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. 2017. "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 = 2017,
month =
}

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

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  • 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-/-), wemore » 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.« less
  • Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. We find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causingmore » degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Therefore, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.« less
  • Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observedmore » that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic differentiaton and expression of BMP2 in PMVECs. • CBDL-rat serum activates the BMP2/smad signaling pathway. • The downregulation of Smurf1 stimulates the accumulation of Smad1/5 in PMVECs. • Noggin reverses partially the myogenic differentiaton in PMVECs.« less
  • Ligation between glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) provides an undefined signal that renders CD4+CD25- effector T cells resistant to the inhibitory effects of CD4+CD25+ regulatory T cells. To understand the structural basis of GITRL function, we have expressed and purified the extracellular domain of human GITR ligand in Escherichia coli. Chromotography and cross-linking studies indicate that human GITRL (hGITRL) exists as dimers and trimers in solution and also can form a supercluster. To gain insight into the nature of GITRL oligomerization, we determined the crystallographic structures of hGITRL, which revealed a loosely associated open trimermore » with a deep cavity at the molecular center and a flexible C-terminal tail bent for trimerization. Moreover, a tetramer of trimers (i.e., supercluster) has also been observed in the crystal, consistent with the cross-linking analysis. Deletion of the C-terminal distal three residues disrupts the loosely assembled trimer and favors the formation of a dimer that has compromised receptor binding and signaling activity. Collectively, our studies identify multiple oligomeric species of hGITRL that possess distinct kinetics of ERK activation. The studies address the functional implications and structural models for a process by which hGITRL utilizes multiple oligomerization states to regulate GITR-mediated signaling during T cell costimulation.« less
  • Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and differentiation into all cell lineages. While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture. Peroxisome-proliferator-activated receptors (PPARs) are ligand-dependent nuclear receptor transcription factors that regulate cell growth and differentiation in many cell types. However, the role of PPARs in the regulation of ES cell growth and differentiation is not known. In this study, we show that LIF induces proliferation and self-renewal of mouse D3-ES cells in culture. However,more » treatment with 15-Deoxy-{delta}{sup 12,14}-Prostaglandin J{sub 2} (15d-PGJ2), a natural ligand for PPAR{gamma}, or all-trans retinoic acid (ATRA) results in a dose-dependent decrease in proliferation and self-renewal in D3-ES cells. Immunoprecipitation and Western blot analyses showed that LIF induces tyrosine phosphorylation of JAK1, TYK2 and STAT3 in 30 min and treatment with 15d-PGJ2 or ATRA results in a dose-dependent decrease in LIF-induced phosphorylation of JAK1 and STAT3 in D3-ES cells. However, treatment of D3-ES cells with Ciglitazone or 15d-PGJ2 for 48 h in culture resulted in a dose-dependent increase in PPAR{gamma} protein expression. These results suggest that PPAR{gamma} agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells.« less