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Title: Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells

Abstract

Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1–/–) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1–/– cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1–/– mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3 days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1–/– 5 day calluses harbor > 2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callusmore » formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21 days post fracture. In conclusion, these data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1–/– mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum.« less

Authors:
; ; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1315852
Alternate Identifier(s):
OSTI ID: 1377772
Report Number(s):
LLNL-JRNL-658875
Journal ID: ISSN 8756-3282; S8756328216300904; PII: S8756328216300904
Grant/Contract Number:  
11-ERD-060; AC52-07NA27344
Resource Type:
Published Article
Journal Name:
Bone
Additional Journal Information:
Journal Name: Bone Journal Volume: 88 Journal Issue: C; Journal ID: ISSN 8756-3282
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Collette, Nicole M., Yee, Cristal S., Hum, Nicholas R., Murugesh, Deepa K., Christiansen, Blaine A., Xie, LiQin, Economides, Aris N., Manilay, Jennifer O., Robling, Alexander G., and Loots, Gabriela G. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells. United States: N. p., 2016. Web. doi:10.1016/j.bone.2016.04.005.
Collette, Nicole M., Yee, Cristal S., Hum, Nicholas R., Murugesh, Deepa K., Christiansen, Blaine A., Xie, LiQin, Economides, Aris N., Manilay, Jennifer O., Robling, Alexander G., & Loots, Gabriela G. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells. United States. doi:10.1016/j.bone.2016.04.005.
Collette, Nicole M., Yee, Cristal S., Hum, Nicholas R., Murugesh, Deepa K., Christiansen, Blaine A., Xie, LiQin, Economides, Aris N., Manilay, Jennifer O., Robling, Alexander G., and Loots, Gabriela G. Fri . "Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells". United States. doi:10.1016/j.bone.2016.04.005.
@article{osti_1315852,
title = {Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells},
author = {Collette, Nicole M. and Yee, Cristal S. and Hum, Nicholas R. and Murugesh, Deepa K. and Christiansen, Blaine A. and Xie, LiQin and Economides, Aris N. and Manilay, Jennifer O. and Robling, Alexander G. and Loots, Gabriela G.},
abstractNote = {Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1–/–) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1–/– cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1–/– mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3 days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1–/– 5 day calluses harbor > 2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callus formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21 days post fracture. In conclusion, these data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1–/– mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum.},
doi = {10.1016/j.bone.2016.04.005},
journal = {Bone},
number = C,
volume = 88,
place = {United States},
year = {2016},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.bone.2016.04.005

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Cited by: 3 works
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Works referencing / citing this record:

A Membranome-Centered Approach Defines Novel Biomarkers for Cellular Subtypes in the Intervertebral Disc
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Anabolic Strategies to Augment Bone Fracture Healing
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A Membranome-Centered Approach Defines Novel Biomarkers for Cellular Subtypes in the Intervertebral Disc
journal, April 2018