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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:
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. 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., 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. doi: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},
journal = {Journal of Bone and Mineral Research},
number = 10,
volume = 33,
place = {United States},
year = {2018},
month = {5}
}

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