Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies

Assefnia, Shahin; Dakshanamurthy, Sivanesan; Auvil, Jaime M. Guidry; Hampel, C.; Anastasiadis, Panos Z.; Kallakury, Bhaskar; Üren, Aykut; Foley, David W.; Brown, Milton L.; Shapiro, Lawrence; Brenner, Michael B.; Haigh, David; Byers, Stephen W.

doi:10.18632/oncotarget.1538

Cited by 57 publications

(53 citation statements)

References 44 publications

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“…20–23, 44–48 Furthermore, Cad-11 promotes osteogenic differentiation in the context of bone growth and development and additionally plays a role in myofibroblastic activation in dermal and pulmonary fibrosis. 49–51 Cad-11 provides the necessary cell-cell tension for aggregation and calcification of valvular myofibroblasts, 25 likely mediated by RhoA and favoring a pro-calcific environment as we show here.…”

Section: Discussionmentioning

confidence: 99%

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

Sung

Bowen

Vaidya

et al. 2016

ATVB

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Objective Calcific aortic valve disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets RhoA and Sox9 in extracellular matrix remodeling and aortic valve calcification. Approach and Results We conditionally overexpressed Cad-11 in murine heart valves using a novel double transgenic Nfatc1Cre;R26-Cad11Tg/Tg mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the aortic valve leaflets. Cad-11 overexpression upregulated downstream targets RhoA and Sox9 in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. Aortic valve interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a ROCK inhibitor attenuated nodule formation, further supporting that Cad-11 driven calcification acts through the small GTPase RhoA/ROCK signaling pathway. Conclusions This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult aortic valve pathogenesis. The findings provide a potential molecular target for clinical treatment.

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Section: Discussionmentioning

confidence: 99%

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

Sung

Bowen

Vaidya

et al. 2016

ATVB

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“…In the context of cancer, OB-cadherin expression is associated with increased migration and metastasis, especially metastasis to bone (Deng et al, 2013). As cell differentiation and migration in cancer and inflammatory disease show some similarities, OB-cadherin has been proposed as a common, possibly therapeutic, target for both types of disease (Assefnia et al, 2014). OB-cadherin plays an important role in inflammation in rheumatoid arthritis; it stimulates synovial fibroblasts to release proinflammatory cytokines upon cadherin engagement (Chang et al, 2011;Ding et al, 2014).…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

“…OB-cadherin plays an important role in inflammation in rheumatoid arthritis; it stimulates synovial fibroblasts to release proinflammatory cytokines upon cadherin engagement (Chang et al, 2011;Ding et al, 2014). Celecoxib, a pharmacological inhibitor of Cox-2 that inhibits inflammation during rheumatoid arthritis, has been shown to bind to OB-cadherin (Assefnia et al, 2014). Inflammation often leads to fibrosis, which is mediated by activated MyoFBs.…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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“…Dysregulated Cad-11 expression contributes to inflammation, cartilage degradation, and metastasis in diseases such as pulmonary fibrosis, rheumatoid arthritis, and multiple cancer types (Assefnia et al, 2014; Lee et al, 2007; Schneider et al, 2012; Tomita et al, 2000). Cad-11 also plays important roles in both cellular migration and differentiation in development, in particular through mediating collective migration and fate specification in neural crest mesenchyme (Becker et al, 2013; Borchers et al, 2001; Kashef et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation

Bowen

Zhou

Sung

et al. 2015

Developmental Biology

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Proper remodeling of the endocardial cushions into thin fibrous valves is essential for gestational progression and long-term function. This process involves dynamic interactions between resident cells and their local environment, much of which is not understood. In this study, we show that deficiency of the cell-cell adhesion protein cadherin-11 (cad-11) results in significant embryonic and perinatal lethality primarily due to valve related cardiac dysfunction. While endocardial to mesenchymal transformation is not abrogated, mesenchymal cells do not homogeneously cellularize the cushions. These cushions remain thickened with disorganized ECM, resulting in pronounced aortic valve insufficiency. Mice that survive to adulthood maintain thickened and stenotic semilunar valves, but interestingly do not develop calcification. Cad-11 −/− aortic valve leaflets contained reduced sox9 activity, β1 integrin expression, and RhoA-GTP activity, suggesting that remodeling defects are due to improper migration and/or cellular contraction. Cad-11 deletion or siRNA knockdown reduced migration, eliminated collective migration, and impaired 3D matrix compaction by aortic valve interstitial cells (VIC). Cad-11 depleted cells in culture contained few filopodia, stress fibers, or contact inhibited locomotion. Transfection of Cad-11 depleted cells with constitutively active RhoA restored cell phenotypes. Together, these results identify cadherin-11 mediated adhesive signaling for proper remodeling of the embryonic semilunar valves.

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Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies

Cited by 57 publications

References 44 publications

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation

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