skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES

Abstract

Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost KO mice ( Sost-/-) causes high bone mass (HBM) similar to sclerosteosis patients. Sost -/- mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to age-matched controls. It has been postulated that the main source of skeletal sclerostin is the osteocyte. To understand the cell-type specific contributions to the HBM phenotype described in Sost-/- mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss-of-function ( SostiCOIN/iCOIN) mice with specific deletions in (1) the limb mesenchyme ( Prx1-Cre; targets osteoprogenitors and their progeny); (2) midstage osteoblasts and their progenitors ( Col1-Cre); (3) mature osteocytes ( Dmp1-Cre); and (4) hypertrophic chondrocytes and their progenitors ( ColX-Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1-Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B-cellmore » defect described in the global KO. Despite WT expression of Sost in the axial skeleton of Prx1-Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1-osteoprogenitor-derived lineages contribute significant amounts of sclerostin protein to the paracrine pool of Sost in bone.« less

Authors:
 [1];  [2];  [1];  [3];  [3];  [2];  [1];  [4];  [5];  [5];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California, Merced, CA (United States)
  2. Univ. of California, Merced, CA (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Regeneron, Tarrytown NY (United States)
  5. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1512582
Report Number(s):
LLNL-JRNL-739165
Journal ID: ISSN 0884-0431; 892575
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Bone and Mineral Research
Additional Journal Information:
Journal Volume: 33; Journal Issue: 10; Journal ID: ISSN 0884-0431
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Yee, Cristal S., Manilay, Jennifer O., Chang, Jiun C., Hum, Nicholas R., Murugesh, Deepa K., Bajwa, Jamila, Mendez, Melanie E., Economides, Aris E., Horan, Daniel J., Robling, Alexander G., and Loots, Gabriela G. Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES. United States: N. p., 2018. Web. doi:10.1002/jbmr.3467.
Yee, Cristal S., Manilay, Jennifer O., Chang, Jiun C., Hum, Nicholas R., Murugesh, Deepa K., Bajwa, Jamila, Mendez, Melanie E., Economides, Aris E., Horan, Daniel J., Robling, Alexander G., & Loots, Gabriela G. Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES. United States. https://doi.org/10.1002/jbmr.3467
Yee, Cristal S., Manilay, Jennifer O., Chang, Jiun C., Hum, Nicholas R., Murugesh, Deepa K., Bajwa, Jamila, Mendez, Melanie E., Economides, Aris E., Horan, Daniel J., Robling, Alexander G., and Loots, Gabriela G. Fri . "Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES". United States. https://doi.org/10.1002/jbmr.3467. https://www.osti.gov/servlets/purl/1512582.
@article{osti_1512582,
title = {Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development: DELETION OF Sost IN MSC-DERIVED LINEAGES},
author = {Yee, Cristal S. and Manilay, Jennifer O. and Chang, Jiun C. and Hum, Nicholas R. and Murugesh, Deepa K. and Bajwa, Jamila and Mendez, Melanie E. and Economides, Aris E. and Horan, Daniel J. and Robling, Alexander G. and Loots, Gabriela G.},
abstractNote = {Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost KO mice (Sost-/-) causes high bone mass (HBM) similar to sclerosteosis patients. Sost-/- mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to age-matched controls. It has been postulated that the main source of skeletal sclerostin is the osteocyte. To understand the cell-type specific contributions to the HBM phenotype described in Sost-/- mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss-of-function (SostiCOIN/iCOIN) mice with specific deletions in (1) the limb mesenchyme (Prx1-Cre; targets osteoprogenitors and their progeny); (2) midstage osteoblasts and their progenitors (Col1-Cre); (3) mature osteocytes (Dmp1-Cre); and (4) hypertrophic chondrocytes and their progenitors (ColX-Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1-Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B-cell defect described in the global KO. Despite WT expression of Sost in the axial skeleton of Prx1-Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1-osteoprogenitor-derived lineages contribute significant amounts of sclerostin protein to the paracrine pool of Sost in bone.},
doi = {10.1002/jbmr.3467},
url = {https://www.osti.gov/biblio/1512582}, journal = {Journal of Bone and Mineral Research},
issn = {0884-0431},
number = 10,
volume = 33,
place = {United States},
year = {2018},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 7 works
Citation information provided by
Web of Science

Figures / Tables:

Table 1 Table 1: Bone Phenotyping by microCT

Save / Share:

Works referenced in this record:

Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization
journal, June 2013


Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength
journal, February 2008


Determinants of serum sclerostin in healthy pre- and postmenopausal women
journal, November 2011


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


Regulation of CXCL12 expression by canonical Wnt signaling in bone marrow stromal cells
journal, May 2011


Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner
journal, November 2013


Serum Sclerostin Levels Negatively Correlate with Parathyroid Hormone Levels and Free Estrogen Index in Postmenopausal Women
journal, April 2010


Osteocyte control of bone formation via sclerostin, a novel BMP antagonist
journal, December 2003


Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF
journal, July 2017


DMP1-targeted Cre Expression in Odontoblasts and Osteocytes
journal, April 2007


SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury: SOST OVEREXPRESSION IMPROVES PTOA OUTCOMES
journal, April 2018


Sclerostin Enhances Adipocyte Differentiation in 3T3-L1 Cells: S
journal, February 2016


The paired-like homeo box gene MHox is required for early events of skeletogenesis in multiple lineages.
journal, May 1995


Changes in bone sclerostin levels in mice after ovariectomy vary independently of changes in serum sclerostin levels
journal, February 2013


Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing Protein
journal, March 2001


WNT signaling in bone homeostasis and disease: from human mutations to treatments
journal, February 2013


Prx1 and 3.2kb Col1a1 promoters target distinct bone cell populations in transgenic mice
journal, January 2014


Bone marrow adipocytes
journal, July 2017


Expression and activity of osteoblast-targeted Cre recombinase transgenes in murine skeletal tissues
journal, January 2004


Adipocyte-Derived Soluble Factor(s) Inhibits Early Stages of B Lymphopoiesis
journal, September 2012


Conditionals by inversion provide a universal method for the generation of conditional alleles
journal, August 2013


Effects of Estrogen on Bone mRNA Levels of Sclerostin and Other Genes Relevant to Bone Metabolism in Postmenopausal Women
journal, January 2014


Expression of Cre recombinase in the developing mouse limb bud driven by aPrxl enhancer
journal, May 2002


SOST/sclerostin, an osteocyte-derived negative regulator of bone formation
journal, June 2005


Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation
journal, August 2014


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


    Works referencing / citing this record:

    Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies
    journal, March 2019


    The Effects of Sclerostin on the Immune System
    journal, January 2020


    The role of osteoblasts in energy homeostasis
    journal, August 2019