Runx2/Smad3 Complex Negatively Regulates TGF-β-Induced Connective Tissue Growth Factor gene Expression in Vascular Smooth Muscle Cells

Ohyama, Yoshiaki; Tanaka, Toru; Shimizu, Tomohiro; Matsui, Hiroki; Sato, Hiroko; Koitabashi, Norimichi; Doi, Hiroshi; Iso, Tatsuya; Arai, M.; Kurabayashi, Masahiko

doi:10.5551/jat.9753

Cited by 18 publications

(19 citation statements)

References 56 publications

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“…RUNX2/Smad 3 interaction stimulated collagen 3 expression in breast cancer cells [61]. Runx2/Smad3 complex negatively regulated endogenous and TGF-beta-induced connective tissue growth factor gene expression in vascular smooth muscle cells [64]. We have found that PC3 cells express Smad −2, -3 and −5 (Additional file 2: Figure S2).…”

Section: Discussionmentioning

confidence: 97%

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

2012

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BackgroundBone loss and pathological fractures are common skeletal complications associated with androgen deprivation therapy and bone metastases in prostate cancer patients. We have previously demonstrated that prostate cancer cells secrete receptor activator of NF-kB ligand (RANKL), a protein essential for osteoclast differentiation and activation. However, the mechanism(s) by which RANKL is produced remains to be determined. The objective of this study is to gain insight into the molecular mechanisms controlling RANKL expression in metastatic prostate cancer cells.ResultsWe show here that phosphorylation of Smad 5 by integrin αvβ3 and RUNX2 by CD44 signaling, respectively, regulates RANKL expression in human-derived PC3 prostate cancer cells isolated from bone metastasis. We found that RUNX2 intranuclear targeting is mediated by phosphorylation of Smad 5. Indeed, Smad5 knock-down via RNA interference and inhibition of Smad 5 phosphorylation by an αv inhibitor reduced RUNX2 nuclear localization and RANKL expression. Similarly, knockdown of CD44 or RUNX2 attenuated the expression of RANKL. As a result, conditioned media from these cells failed to support osteoclast differentiation in vitro. Immunohistochemistry analysis of tissue microarray sections containing primary prostatic tumor (grade2-4) detected predominant localization of RUNX2 and phosphorylated Smad 5 in the nuclei. Immunoblotting analyses of nuclear lysates from prostate tumor tissue corroborate these observations.ConclusionsCollectively, we show that CD44 signaling regulates phosphorylation of RUNX2. Localization of RUNX2 in the nucleus requires phosphorylation of Smad-5 by integrin αvβ3 signaling. Our results suggest possible integration of two different pathways in the expression of RANKL. These observations imply a novel mechanistic insight into the role of these proteins in bone loss associated with bone metastases in patients with prostate cancer.

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Section: Discussionmentioning

confidence: 97%

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

2012

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“…Evidence from multiple sources indicates that experimental modulation of TGF-β activity, or TGF-β responses, changes the course of atherosclerosis [45]. Runx2/Smad3 complex negatively regulates TGF-β-induced connective tissue growth factor gene expression in vascular smooth muscle cells [46]. In complicated abdominal aortic aneurysm, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture [47].…”

Section: Discussionmentioning

confidence: 99%

Correlation of Lower Concentrations of Hydrogen Sulfide with Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

Feng²,

Zhang³

et al. 2014

Blood Purif

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Background/Aims: To explore the relationship between hydrogen sulfide (H₂S) and uremic accelerated atherosclerosis (UAAS) in chronic hemodialysis patients with diabetic nephropathy (CHD/DN). Methods: A total of 36 CHD/DN and 32 chronic hemodialyzed non-diabetic patients with chronic glomerulonephritis (CHD/non-DN) were studied. Plasma H₂S was measured with a sulfide sensitive electrode. Results: Plasma H₂S in CHD/DN was significantly lower than that in CHD/non-DN patients. Plasma H₂S was positively correlated with plasma TGF-β1, and negatively correlated with MMP-12 in CHD/DN patients. CHD/DN patients exhibited higher CCA-IMT, hsCRP, and lower H₂S levels than in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was negatively correlated with plasma H₂S, and positively correlated with hsCRP and LDL. On multiple regression analysis, H₂S levels exhibited independent association with IMT in CHD/DN patients. Conclusions: These findings suggest possible linkage between H₂S metabolism and TGF-β/Smad signaling pathway modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients.

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“…25, 26 We therefore tested if Olfm2 is involved in the Runx2 activity in the SRF-Myocd interaction. Interestingly, PDGF-BB only induced a modest increase in Runx2 expression (1.5 fold) 24 h after the induction (Figure 5A and 5B).…”

Section: Resultsmentioning

confidence: 99%

“…22–24 Recent studies have revealed that runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor, serves as a corepressor independent of its DNA binding by interacting with SRF and disrupting the formation of SRF/Myocd complex, which contributes to the phenotypic modulation of SMCs. 25, 26 The precise molecular mechanisms whereby Runx2 interferes with SRF/Myocd complex formation, however, remain largely unknown.…”

mentioning

confidence: 99%

Olfactomedin 2 Regulates Smooth Muscle Phenotypic Modulation and Vascular Remodeling Through Mediating Runt-Related Transcription Factor 2 Binding to Serum Response Factor

Shi

Cui

et al. 2017

ATVB

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Objective The objective of this study is to investigate the role and underlying mechanism of Olfactomedin 2 (Olfm2) in SMC phenotypic modulation and vascular remodeling. Approach and Results Platelet-derived growth factor-BB (PDGF-BB) induces Olfm2 expression in primary SMCs while modulating SMC phenotype as shown by the down-regulation of SMC marker proteins. Knockdown of Olfm2 blocks PDGF-BB-induced SMC phenotypic modulation, proliferation and migration. Conversely, Olfm2 overexpression inhibits SMC marker expression. Mechanistically, Olfm2 promotes the interaction of serum response factor with the runt-related transcription factor 2 that is induced by PDGF-BB, leading to a decreased interaction between serum response factor and myocardin, causing a repression of SMC marker gene transcription and consequently SMC phenotypic modulation. Animal studies show that Olfm2 is up-regulated in balloon-injured rat carotid arteries. Knockdown of Olfm2 effectively inhibits balloon injury-induced neointima formation. Importantly, knockout of Olfm2 in mice profoundly suppresses wire injury-induced neointimal hyperplasia while restoring SMC contractile protein expression, suggesting that Olfm2 plays a critical role in SMC phenotypic modulation in vivo. Conclusions Olfm2 is a novel factor mediating SMC phenotypic modulation. Thus, Olfm2 may be a potential target for treating injury-induced proliferative vascular diseases.

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Runx2/Smad3 Complex Negatively Regulates TGF-β-Induced Connective Tissue Growth Factor gene Expression in Vascular Smooth Muscle Cells

Cited by 18 publications

References 56 publications

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a Runx2/Smad 5/receptor activator of NF-κB ligand signaling axis

Correlation of Lower Concentrations of Hydrogen Sulfide with Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

Olfactomedin 2 Regulates Smooth Muscle Phenotypic Modulation and Vascular Remodeling Through Mediating Runt-Related Transcription Factor 2 Binding to Serum Response Factor

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