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Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification
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Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification
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Journal Article
Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification
2013
Overview
In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of
GNAS
, this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia.
Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gα
s
restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in
GNAS
, which encodes Gα
s
, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that
GNAS
gain-of-function mutations upregulate WNT–β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gα
s
as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt–β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by
GNAS
inactivation.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Bone Diseases, Metabolic - genetics
/ Bone Diseases, Metabolic - metabolism
/ Bone Diseases, Metabolic - pathology
/ Bones
/ Cellular signal transduction
/ Female
/ Genetics
/ GTP-Binding Protein alpha Subunits, Gs - deficiency
/ GTP-Binding Protein alpha Subunits, Gs - genetics
/ Hedgehog Proteins - antagonists & inhibitors
/ Hedgehog Proteins - genetics
/ Hedgehog Proteins - metabolism
/ Humans
/ Male
/ Mice
/ Mutation
/ Ossification, Heterotopic - genetics
/ Ossification, Heterotopic - metabolism
/ Ossification, Heterotopic - pathology
/ Skin Diseases, Genetic - genetics
/ Skin Diseases, Genetic - metabolism
