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Wnt/?-catenin signaling is differentially regulated by G? proteins and contributes to fibrous dysplasia.

ABSTRACT: Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/?-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major G? protein families (G?(s), G?(i/o), G?(q/11), and G?(12/13)) with the Wnt/?-catenin signaling pathway and identify a causative role of Wnt/?-catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating G?(s) mutations that cause FD potentiated Wnt/?-catenin signaling, and removal of G?(s) led to reduced Wnt/?-catenin signaling and decreased bone formation. We further show that activation of Wnt/?-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of ?-catenin levels rescued differentiation defects of FD patient-derived stromal cells. G? proteins may act at the level of ?-catenin destruction complex assembly by binding Axin. Our results indicate that activated G? proteins differentially regulate Wnt/?-catenin signaling but, importantly, are not required core components of Wnt/?-catenin signaling. Our data suggest that activated G? proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/?-catenin signaling strength.

SUBMITTER: Regard JB

PROVIDER: S-EPMC3250124 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia.

Regard Jean B JB Cherman Natasha N Palmer Daniel D Kuznetsov Sergei A SA Celi Francesco S FS Guettier Jean-Marc JM Chen Min M Bhattacharyya Nisan N Wess Jurgen J Coughlin Shaun R SR Weinstein Lee S LS Collins Michael T MT Robey Pamela G PG Yang Yingzi Y

Proceedings of the National Academy of Sciences of the United States of America 20111121 50

Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/β-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can a ...[more]

PMID: 22106277

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Project description:The goal of this study was to use protein array analysis to investigate temporal regulation of stimulated cytokine expression in trigeminal ganglia and the spinal trigeminal nucleus in response to co-treatment of sumatriptan and naproxen sodium or individual drug.Activation of neurons and glia in trigeminal ganglia and the spinal trigeminal nucleus leads to increased levels of cytokines that promote peripheral and central sensitization, which are key events in migraine pathology. While recent clinical studies have provided evidence that a combination of sumatriptan and naproxen sodium is more efficacious in treating migraine than either drug alone, it is not well understood why the combination therapy is superior to monotherapy.Male Sprague-Dawley rats were left untreated (control), injected with capsaicin, or pretreated with sumatriptan/naproxen, sumatriptan, or naproxen for 1 hour prior to capsaicin. Trigeminal ganglia and the spinal trigeminal nucleus were isolated 2 and 24 hours after capsaicin or drug treatment, and levels of 90 proteins were determined using a RayBio® Label-Based Rat Antibody Array (RayBiotech, Norcross, GA, USA).Capsaicin stimulated a >3-fold increase in expression of the majority of cytokines in trigeminal ganglia at 2 hours that was sustained at 24 hours. Significantly, treatment with sumatriptan/naproxen almost completely abolished the stimulatory effects of capsaicin at 2 and 24 hours. Capsaicin stimulated >3-fold expression of more proteins in the spinal trigeminal nucleus at 24 hours when compared to 2 hours. Similarly, sumatriptan/naproxen abolished capsaicin stimulation of proteins in the spinal trigeminal nucleus at 2 hours and greatly suppressed protein expression 24 hours post-capsaicin injection. Interestingly, treatment with sumatriptan alone suppressed expression of different cytokines in trigeminal ganglia and the spinal trigeminal nucleus than repressed by naproxen sodium.We found that the combination of sumatriptan/naproxen was effective in blocking capsaicin stimulation of pro-inflammatory proteins implicated in the development of peripheral and central sensitization in response to capsaicin activation of trigeminal neurons. Based on our findings that sumatriptan and naproxen regulate expression of different proteins in trigeminal ganglia and the spinal trigeminal nucleus, we propose that these drugs function on therapeutically distinct cellular targets to suppress inflammation and pain associated with migraine.

Dataset Information

Wnt/?-catenin signaling is differentially regulated by G? proteins and contributes to fibrous dysplasia.

Publications

Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia.

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