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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.

Project description:BackgroundN-myc downstream regulated gene 1 (NDRG1) plays a role in a variety of biological processes including differentiation of osteoclasts. However, it is not known if and how NDRG1 regulates osteogenic differentiation of marrow stromal progenitor cells.MethodsGene expression profiling analysis was performed to study the expression level of Ndrg1 during osteogenic and adipogenic differentiation. Gain-of-function and/or loss-of function experiments were carried out to study the role of NDRG1 in the proliferation and differentiation of marrow stromal progenitor cells and the mechanism underlying the function was investigated. Finally, in vivo transfection of Ndrg1 siRNA was done and its effect on osteogenic and adipogenic differentiation in mice was explored.ResultsGene expression profiling analysis revealed that NDRG1 level was regulated during osteogenic and adipogenic differentiation of progenitor cells. The functional experiments demonstrated that NDRG1 negatively regulated the cell growth, and reciprocally modulated the osteogenic and adipogenic commitment of marrow stromal progenitor cells, driving the cells to differentiate toward adipocytes at the expense of osteoblast differentiation. Moreover, NDRG1 interacted with low-density lipoprotein receptor-related protein 6 (LRP6) in the stromal progenitor cells and inactivated the canonical Wnt/β-catenin signaling cascade. Furthermore, the impaired differentiation of progenitor cells induced by Ndrg1 siRNA could be attenuated when β-catenin was simultaneously silenced. Finally, in vivo transfection of Ndrg1 siRNA to the marrow of mice prevented the inactivation of canonical Wnt signaling in the BMSCs of ovariectomized mice, and ameliorated the reduction of osteoblasts on the trabeculae and increase of fat accumulation in the marrow observed in the ovariectomized mice.ConclusionThis study has provided evidences that NDRG1 plays a role in reciprocally modulating osteogenic and adipogenic commitment of marrow stromal progenitor cells through inactivating canonical Wnt signaling.

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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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