Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

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Abstract

Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2016

Fingerprint

Glucocorticoids
Osteoporosis
Catenins
Osteogenesis
Bone and Bones
Bone Resorption
Osteoprotegerin
Cyclin D1
Iatrogenic Disease
Osteocytes
Wnt Signaling Pathway
Bone Fractures
Apoptosis
Gene Expression

Keywords

  • Corticosteroids
  • Genetic animal models
  • Molecular pathways - remodeling
  • Osteoporosis
  • Wnt/β-catenin/LRPS

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{f869fe0eea88447381940d8cdfe3ccbb,
title = "Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin",
abstract = "Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling.",
keywords = "Corticosteroids, Genetic animal models, Molecular pathways - remodeling, Osteoporosis, Wnt/β-catenin/LRPS",
author = "Amy Sato and Meloney Cregor and Jesus Delgado-Calle and Condon, {Keith W.} and Matthew Allen and Munro Peacock and Lilian Plotkin and Teresita Bellido",
year = "2016",
doi = "10.1002/jbmr.2869",
language = "English (US)",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

AU - Sato, Amy

AU - Cregor, Meloney

AU - Delgado-Calle, Jesus

AU - Condon, Keith W.

AU - Allen, Matthew

AU - Peacock, Munro

AU - Plotkin, Lilian

AU - Bellido, Teresita

PY - 2016

Y1 - 2016

N2 - Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling.

AB - Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling.

KW - Corticosteroids

KW - Genetic animal models

KW - Molecular pathways - remodeling

KW - Osteoporosis

KW - Wnt/β-catenin/LRPS

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U2 - 10.1002/jbmr.2869

DO - 10.1002/jbmr.2869

M3 - Article

C2 - 27163932

AN - SCOPUS:84973333548

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

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