Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation

Nakashima, Aiko; Tamura, Masato

doi:10.2741/1912

Cited by 30 publications

(16 citation statements)

References 60 publications

(72 reference statements)

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“…To test whether the HGF-induced EMT causes activation of Wnt target genes, we looked at the expression levels of both the potential endogenous target MMP-13 [27], [28] and the transfected TOPflash reporter in MDCK cells treated with cycloheximide for 6 hours and/or HGF using quantitative RT-PCR, and found that HGF increases the transcription of these genes even in the presence of cycloheximide (Fig. 2I).…”

Section: Resultsmentioning

confidence: 99%

A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

Howard¹,

Deroo²,

et al. 2011

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The Wnt/β-catenin signalling pathway shares a key component, β-catenin, with the cadherin-based adhesion system. The signalling function of β-catenin is conferred by a soluble cytoplasmic pool that is unstable in the absence of a Wnt signal, whilst the adhesion function is based on a cadherin-bound, stable pool at the membrane. The cadherin complex is dynamic, allowing for cell-cell rearrangements such as epithelial-mesenchymal transition (EMT), where the complex turns over through internalisation. Potential interplay between the two pools remains poorly understood, but cadherins are generally considered negative regulators of Wnt signalling because they sequester cytoplasmic β-catenin. Here we explore how cellular changes at EMT affect the signalling capacity of β-catenin using two models of EMT: hepatocyte growth factor (HGF) treatment of MDCK cells, and gastrulation in embryonic development. We show that EMT not only provides a pool of signalling-competent β-catenin following internalisation of cadherin, but also significantly facilitates activation of the Wnt pathway in response to both Wnt signals and exogenous β-catenin. We further demonstrate that availability of β-catenin in the cytoplasm does not necessarily correlate with Wnt/β-catenin pathway activity, since blocking endocytosis or depleting endogenous cadherin abolishes pathway activation despite the presence of β-catenin in the cytoplasm. Lastly we present data suggesting that cadherins are required for augmented activation of the Wnt/β-catenin pathway in vivo. This suggests that cadherins play a crucial role in β-catenin-dependent transcription.

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Section: Resultsmentioning

confidence: 99%

A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

Howard¹,

Deroo²,

et al. 2011

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“…These data, combined with the elevated expression levels of BMP-9 (Gdf-2), and a 2.36-fold elevation of BMP-2, suggest that activation of the BMP signaling pathway may play a significant role in aortic dilatation and aneurysm formation. In fact, treatment of C2C12 fibroblasts with BMP-2 has previously been shown to result in the potent induction of MMP-13 and concomitant repression of TIMP-1 [26], both of which would serve to enhance TAA formation in the present model system. Together, the regulation of ligand expression and signaling may serve to stimulate other signaling pathways that contribute to aneurysm development or drive a process of differentiation capable of altering the phenotype of resident vascular cells.…”

Section: Discussionmentioning

confidence: 98%

Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm

et al. 2008

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Objective: Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-β) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-β signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-β signaling occur during aneurysm formation was tested in a murine model of TAA. Methods: TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-β superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice. Results: QPCR revealed increased expression of TGF-β superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-β receptor_II, Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-β receptor_I and Smad4 were decreased from control values, while ALK-1 levels remained unchanged. Conclusions: These alterations in the TGF-β pathway suggest a mechanism by which primary signaling is switched from a TGF-βR_I/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation.

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“…Activation of β-catenin in maturing chondrocytes is associated with increased expression of multiple matrix metalloproteinases including MMP-3, MMP-9 and MMP-1354. Other studies performed in cancer cells have shown that canonical Wnt-β-catenin signaling can regulate the expression of MMP-9 and MMP-1363,64. Both dysregulated expression of matrix metalloproteinases and cyclo-oxygenase-2 have been implicated in the pathophysiology of osteoarthritis65,66.…”

Section: Discussionmentioning

confidence: 99%

Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes

Ohba

Lanigan

Roessler

2010

Osteoarthritis and Cartilage

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Objective Differentiated articular chondrocytes express a functional isoform of the leptin receptor (LRb); however, leptin-LRb signaling in these cells is poorly understood. We hypothesized that leptin-LRb signaling in articular chondrocytes functions to modulate canonical Wnt signaling events by altering the expression of Frizzled receptors. Methods Human chondrocyte cell lines and primary articular chondrocytes were grown in serum containing growth media for 24 hrs, followed by a media change to DMEM containing 1% Nutridoma-SP to obtain a serum-deficient environment for 24 hours before treatment. Treatments included recombinant human leptin (10–100 nM), recombinant human IL-6 (0.3-3 nM), or recombinant human erythropoietin (10 mU/ml). Cells were harvested 30 min to 48 hrs after treatment and whole cell lysates were analyzed using immunoblots or luciferase assays. Results Treatment of cells with leptin resulted in activation of JAK2 and subsequent phosphorylation of specific tyrosine residues on LRb, followed by dose- and time-dependent increases in the expression of Frizzled-1 (Fzd1) and Frizzled-7 (Fzd7). Leptin-mediated increases in the expression of Fzd1 and Fzd7 were blocked by pre-treatment with the protein synthesis inhibitor cycloheximide or the JAK2 inhibitor AG490. Experiments using a series of hybrid erythropoietin extracellular domain-leptin intracellular domain receptors (ELR) harboring mutations of specific tyrosine residues in the cytoplasmic tail showed that increases in the expression of Fzd1 and Fzd7 were dependent on LRb-mediated phosphorylation of STAT3, but not ERK1/2 or STAT5. Leptin pre-treatment of chondrocytes prior to Wnt-3a stimulation resulted in an increased magnitude of canonical Wnt signaling. Conclusion These experiments show that leptin-LRb signaling in articular chondrocytes modulates expression of canonical Wnt signaling receptors and suggests that direct cross-talk between these pathways is important in determining chondrocyte homeostasis.

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Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation

Cited by 30 publications

References 60 publications

A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm

Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes

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