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Title: Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice

Abstract

ABSTRACT CXCL12 is abundantly expressed in reticular cells associated with the perivascular niches of the bone marrow (BM) and is indispensable for B lymphopoiesis. Cxcl12 promotes osteoclastogenesis and has been implicated in pathologic bone resorption. We had shown earlier that estrogen receptor α deletion in osteoprogenitors and estrogen deficiency in mice increase Cxcl12 mRNA and protein levels in the BM plasma, respectively. We have now generated female and male mice with conditional deletion of a Cxcl12 allele in Prrx1 targeted cells ( Cxcl12 ∆Prrx1 ) and show herein that they have a 90% decrease in B lymphocytes but increased erythrocytes and adipocytes in the marrow. Ovariectomy increased the expression of Cxcl12 and B‐cell number in the Cxcl12 f/f control mice, but these effects were abrogated in the Cxcl12 ∆Prrx1 mice. Cortical bone mass was not affected in Cxcl12 ∆Prrx1 mice. Albeit, the cortical bone loss caused by ovariectomy was greatly attenuated. Most unexpectedly, the rate of bone turnover in sex steroid–sufficient female or male Cxcl12 ∆Prrx1 mice was dramatically increased, as evidenced by a more than twofold increase in several osteoblast‐ and osteoclast‐specific mRNAs, as well as increased mineral apposition and bone formation rate and increased osteoclast number in themore » endosteal surface. The magnitude of the Cxcl12 ∆Prrx1 ‐induced changes were much greater than those caused by ovariectomy or orchidectomy in the Cxcl12 f/f mice. These results strengthen the evidence that CXCL12 contributes to the loss of cortical bone mass caused by estrogen deficiency. Moreover, they reveal for the first time that in addition to its effects on hematopoiesis, CXCL12 restrains bone turnover—without changing the balance between resorption and formation—by suppressing osteoblastogenesis and the osteoclastogenesis support provided by cells of the osteoblast lineage. © 2020 American Society for Bone and Mineral Research.« less

Authors:
ORCiD logo [1]; ORCiD logo [1];  [2];  [1];  [3]; ORCiD logo [3]
  1. Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences Little Rock AR USA
  2. Department of Orthopedic Surgery University of Arkansas for Medical Sciences Little Rock AR USA
  3. Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences Little Rock AR USA, Department of Orthopedic Surgery University of Arkansas for Medical Sciences Little Rock AR USA, The Central Arkansas Veterans Healthcare System Little Rock AR USA
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1647404
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Journal of Bone and Mineral Research
Additional Journal Information:
Journal Name: Journal of Bone and Mineral Research Journal Volume: 35 Journal Issue: 8; Journal ID: ISSN 0884-0431
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English

Citation Formats

Ponte, Filipa, Kim, Ha‐Neui, Iyer, Srividhya, Han, Li, Almeida, Maria, and Manolagas, Stavros C. Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice. United States: N. p., 2020. Web. doi:10.1002/jbmr.4002.
Ponte, Filipa, Kim, Ha‐Neui, Iyer, Srividhya, Han, Li, Almeida, Maria, & Manolagas, Stavros C. Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice. United States. https://doi.org/10.1002/jbmr.4002
Ponte, Filipa, Kim, Ha‐Neui, Iyer, Srividhya, Han, Li, Almeida, Maria, and Manolagas, Stavros C. Wed . "Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice". United States. https://doi.org/10.1002/jbmr.4002.
@article{osti_1647404,
title = {Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice},
author = {Ponte, Filipa and Kim, Ha‐Neui and Iyer, Srividhya and Han, Li and Almeida, Maria and Manolagas, Stavros C.},
abstractNote = {ABSTRACT CXCL12 is abundantly expressed in reticular cells associated with the perivascular niches of the bone marrow (BM) and is indispensable for B lymphopoiesis. Cxcl12 promotes osteoclastogenesis and has been implicated in pathologic bone resorption. We had shown earlier that estrogen receptor α deletion in osteoprogenitors and estrogen deficiency in mice increase Cxcl12 mRNA and protein levels in the BM plasma, respectively. We have now generated female and male mice with conditional deletion of a Cxcl12 allele in Prrx1 targeted cells ( Cxcl12 ∆Prrx1 ) and show herein that they have a 90% decrease in B lymphocytes but increased erythrocytes and adipocytes in the marrow. Ovariectomy increased the expression of Cxcl12 and B‐cell number in the Cxcl12 f/f control mice, but these effects were abrogated in the Cxcl12 ∆Prrx1 mice. Cortical bone mass was not affected in Cxcl12 ∆Prrx1 mice. Albeit, the cortical bone loss caused by ovariectomy was greatly attenuated. Most unexpectedly, the rate of bone turnover in sex steroid–sufficient female or male Cxcl12 ∆Prrx1 mice was dramatically increased, as evidenced by a more than twofold increase in several osteoblast‐ and osteoclast‐specific mRNAs, as well as increased mineral apposition and bone formation rate and increased osteoclast number in the endosteal surface. The magnitude of the Cxcl12 ∆Prrx1 ‐induced changes were much greater than those caused by ovariectomy or orchidectomy in the Cxcl12 f/f mice. These results strengthen the evidence that CXCL12 contributes to the loss of cortical bone mass caused by estrogen deficiency. Moreover, they reveal for the first time that in addition to its effects on hematopoiesis, CXCL12 restrains bone turnover—without changing the balance between resorption and formation—by suppressing osteoblastogenesis and the osteoclastogenesis support provided by cells of the osteoblast lineage. © 2020 American Society for Bone and Mineral Research.},
doi = {10.1002/jbmr.4002},
journal = {Journal of Bone and Mineral Research},
number = 8,
volume = 35,
place = {United States},
year = {2020},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
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https://doi.org/10.1002/jbmr.4002

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Works referenced in this record:

CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance
journal, February 2013

  • Greenbaum, Adam; Hsu, Yen-Michael S.; Day, Ryan B.
  • Nature, Vol. 495, Issue 7440
  • DOI: 10.1038/nature11926

Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual
journal, December 2012

  • Almeida, Maria; Iyer, Srividhya; Martin-Millan, Marta
  • Journal of Clinical Investigation, Vol. 123, Issue 1
  • DOI: 10.1172/JCI65910

Estrogens and Androgens in Skeletal Physiology and Pathophysiology
journal, January 2017


Sex Steroid Actions in Male Bone
journal, September 2014

  • Vanderschueren, Dirk; Laurent, Michaël R.; Claessens, Frank
  • Endocrine Reviews, Vol. 35, Issue 6
  • DOI: 10.1210/er.2014-1024

Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches
journal, February 2013


The role of the chemokine CXCL12 in osteoclastogenesis
journal, April 2007

  • Gronthos, Stan; Zannettino, Andrew C. W.
  • Trends in Endocrinology & Metabolism, Vol. 18, Issue 3
  • DOI: 10.1016/j.tem.2007.02.002

Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow.
journal, September 1994

  • Masuzawa, T.; Miyaura, C.; Onoe, Y.
  • Journal of Clinical Investigation, Vol. 94, Issue 3
  • DOI: 10.1172/JCI117424

Mesenchymal stem cell expression of stromal cell-derived factor-1β augments bone formation in a model of local regenerative therapy: SDF-1β ENHANCES BMSC-MEDIATED BONE FORMATION
journal, October 2014

  • Herberg, Samuel; Kondrikova, Galina; Hussein, Khaled A.
  • Journal of Orthopaedic Research, Vol. 33, Issue 2
  • DOI: 10.1002/jor.22749

Elevated Serum Levels of Stromal-Derived Factor-1α Are Associated with Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients
journal, March 2005


Increased B lymphopoiesis in genetically sex steroid-deficient hypogonadal (hpg) mice.
journal, August 1994

  • Smithson, G.; Beamer, W. G.; Shultz, K. L.
  • The Journal of Experimental Medicine, Vol. 180, Issue 2
  • DOI: 10.1084/jem.180.2.717

Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways
journal, October 2014


Receptor Activator of Nuclear Factor κB Ligand (RANKL) Protein Expression by B Lymphocytes Contributes to Ovariectomy-induced Bone Loss
journal, July 2012

  • Onal, Melda; Xiong, Jinhu; Chen, Xinrong
  • Journal of Biological Chemistry, Vol. 287, Issue 35
  • DOI: 10.1074/jbc.M112.377945

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion
journal, October 2011


Update on Estrogens and the Skeleton
journal, August 2010

  • Khosla, Sundeep
  • The Journal of Clinical Endocrinology & Metabolism, Vol. 95, Issue 8
  • DOI: 10.1210/jc.2010-0856

Osteoimmunology and Its Implications for Transplantation: Osteoimmunology
journal, September 2013

  • Pacifici, R.
  • American Journal of Transplantation, Vol. 13, Issue 9
  • DOI: 10.1111/ajt.12380

RANKL (Receptor Activator of NFκB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice
journal, October 2016

  • Fujiwara, Yuko; Piemontese, Marilina; Liu, Yu
  • Journal of Biological Chemistry, Vol. 291, Issue 48
  • DOI: 10.1074/jbc.M116.742452

Stromal Cell-Derived Factor-1β Mediates Cell Survival through Enhancing Autophagy in Bone Marrow-Derived Mesenchymal Stem Cells
journal, March 2013


Stromal Cell-Derived Factor-1 (SDF-1) Recruits Osteoclast Precursors by Inducing Chemotaxis, Matrix Metalloproteinase-9 (MMP-9) Activity, and Collagen Transmigration
journal, August 2003

  • Yu, Xuefeng; Huang, Yuefang; Collin-Osdoby, Patricia
  • Journal of Bone and Mineral Research, Vol. 18, Issue 8
  • DOI: 10.1359/jbmr.2003.18.8.1404

CXCL12/CXCR4 signaling in the osteoblast regulates the mesenchymal stem cell and osteoclast lineage populations
journal, May 2013

  • Shahnazari, Mohammad; Chu, Vivian; Wronski, Thomas J.
  • The FASEB Journal, Vol. 27, Issue 9
  • DOI: 10.1096/fj.12-225763

Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee
journal, December 2012

  • Dempster, David W.; Compston, Juliet E.; Drezner, Marc K.
  • Journal of Bone and Mineral Research, Vol. 28, Issue 1
  • DOI: 10.1002/jbmr.1805

Human osteoclasts express different CXC chemokines depending on cell culture substrate: molecular and immunocytochemical evidence of high levels of CXCL10 and CXCL12
journal, November 2003

  • Grassi, Francesco; Piacentini, Anna; Cristino, Sandra
  • Histochemistry and Cell Biology, Vol. 120, Issue 5
  • DOI: 10.1007/s00418-003-0587-3

Conditional Inactivation of the CXCR4 Receptor in Osteoprecursors Reduces Postnatal Bone Formation Due to Impaired Osteoblast Development
journal, June 2011

  • Zhu, Wei; Liang, Gang; Huang, Zhiping
  • Journal of Biological Chemistry, Vol. 286, Issue 30
  • DOI: 10.1074/jbc.M111.250985

Maintenance of the Hematopoietic Stem Cell Pool by CXCL12-CXCR4 Chemokine Signaling in Bone Marrow Stromal Cell Niches
journal, December 2006


Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
journal, December 2001


Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells
journal, May 2006

  • Kollet, Orit; Dar, Ayelet; Shivtiel, Shoham
  • Nature Medicine, Vol. 12, Issue 6
  • DOI: 10.1038/nm1417

FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation
journal, April 2014

  • Bartell, Shoshana M.; Kim, Ha-Neui; Ambrogini, Elena
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms4773

AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells
journal, August 2014


The hematopoietic stem cell in its place
journal, March 2006

  • Adams, Gregor B.; Scadden, David T.
  • Nature Immunology, Vol. 7, Issue 4
  • DOI: 10.1038/ni1331

CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients
journal, January 2004

  • Grassi, Francesco; Cristino, Sandra; Toneguzzi, Stefania
  • Journal of Cellular Physiology, Vol. 199, Issue 2
  • DOI: 10.1002/jcp.10445

Guidelines for assessment of bone microstructure in rodents using micro-computed tomography
journal, June 2010

  • Bouxsein, Mary L.; Boyd, Stephen K.; Christiansen, Blaine A.
  • Journal of Bone and Mineral Research, Vol. 25, Issue 7
  • DOI: 10.1002/jbmr.141