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18. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

Author

Liakouli, Vasiliki, primary, Elies, Jacobo, additional, El-Sherbiny, Yasser Mohamed, additional, Scarcia, Margherita, additional, Grant, Gary, additional, Abignano, Giuseppina, additional, Derrett-Smith, Emma C, additional, Esteves, Filomena, additional, Cipriani, Paola, additional, Emery, Paul, additional, Denton, Christopher P, additional, Giacomelli, Roberto, additional, Mavria, Georgia, additional, and Del Galdo, Francesco, additional

Published
2017
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19. Limited cutaneous systemic sclerosis skin demonstrates distinct molecular subsets separated by a cardiovascular development gene expression signature

Author

Derrett-Smith, Emma C., primary, Martyanov, Viktor, additional, Chighizola, Cecilia B., additional, Moinzadeh, Pia, additional, Campochiaro, Corrado, additional, Khan, Korsa, additional, Wood, Tammara A., additional, Meroni, Pier Luigi, additional, Abraham, David J., additional, Ong, Voon H., additional, Lafyatis, Robert, additional, Whitfield, Michael L., additional, and Denton, Christopher P., additional

Published
2017
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21. Limited cutaneous systemic sclerosis skin demonstrates distinct molecular subsets separated by a cardiovascular development gene expression signature

Author

Derrett-Smith, Emma C., Martyanov, Viktor, Chighizola, Cecilia B., Moinzadeh, Pia, Campochiaro, Corrado, Khan, Korsa, Wood, Tammara A., Meroni, Pier Luigi, Abraham, David J., Ong, Voon H., Lafyatis, Robert, Whitfield, Michael L., Denton, Christopher P., Derrett-Smith, Emma C., Martyanov, Viktor, Chighizola, Cecilia B., Moinzadeh, Pia, Campochiaro, Corrado, Khan, Korsa, Wood, Tammara A., Meroni, Pier Luigi, Abraham, David J., Ong, Voon H., Lafyatis, Robert, Whitfield, Michael L., and Denton, Christopher P.

Abstract

Background: Systemic sclerosis (SSc; scleroderma) is an uncommon autoimmune rheumatic disease characterised by autoimmunity, vasculopathy and fibrosis. Gene expression profiling distinguishes scleroderma from normal skin, and can detect different subsets of disease, with potential to identify prognostic biomarkers of organ involvement or response to therapy. We have performed gene expression profiling in skin samples from patients with limited cutaneous SSc (lcSSc). Methods: Total RNA was extracted from clinically uninvolved skin biopsies of 15 patients with lcSSc and 8 healthy controls (HC). Gene expression profiling was performed on a DNA oligonucleotide microarray chip. Differentially expressed genes (DEG) were identified using significance analysis of microarrays (SAM). Functional enrichment analysis of gene signatures was done via g:Profiler. Results: There were 218 DEG between lcSSc and HC samples (false discovery rate <10%): 181/218 DEG were upregulated in lcSSc samples. Hierarchical clustering of DEG suggested the presence of two separate groups of lcSSc samples: limited 1 and limited 2. The limited-1 group (13 samples, 10 unique patients) showed upregulation of genes involved in cell adhesion, cardiovascular system (CVS) development, extracellular matrix and immune and inflammatory response. The CVS development signature was of particular interest as its genes showed very strong enrichment in response to wounding, response to transforming growth factor (TGF)-beta and kinase cascade. Neither limited-2 samples (six samples, five unique patients) nor HC samples showed functional enrichment. There were no significant differences in demographic or clinical parameters between these two groups. These results were confirmed using a second independent cohort. Conclusions: Our study suggests the presence of molecular subsets in lcSSc based on gene expression profiling of biopsies from uninvolved skin. This may reflect important differences in pathogenesis within thes

Published
2017

22. Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort

Author

Nihtyanova, Svetlana, Ong, Voon, Black, Carol, Denton, Chris, Lutalo, Pamela, Shattles, Warren, Jones, Hugh, Nouri, Reem, Hepburn, Alastair, Chard, Michael, Horwood, Natalie, Lynn, Myo, Duke, Oliver, Kiely, Patrick, Zouita, Louisa, Davies, Ursula, Hughes, Rod, Lloyd, Mark, Nikitorowicz Buniak, Joanna, Shiwen, Xu, Abraham, David, Stratton, Richard, Hügle, Thomas, Schuetz, Philipp, Daikeler, Thomas, Tyndall, Alan, Matucci-Cerinic, Marco, Walker, Ulrich A., van Laar, Jacob M., Pauling, John D., Flower, Victoria, McHugh, Neil, Liu, Shangxi, Leask, Andrew, Aden, Nima, Khan, Korsa, Hoyles, Rachel, Bhagat, Shweta, Drummond, Tom, Goh, Cyndi, Busch, Robert, Hall, Frances, Meyer, Paul, Moinzadeh, Pia, Krieg, Thomas, Hellmich, Martin, Brinckmann, Juergen, Neumann, Elena, Mueller-Ladner, Ulf, Kreuter, Alexander, Dumitresco, Daniel, Rosenkranz, Stefan, Hunzelmann, Nicolas, Binai, Nadine, Huegle, Thomas, van Laar, Jaap, Sonnylal, S., Tam, A., Jones, H., Leask, A., Norman, J., Denton, C., de Crombrugghe, B., Abraham, D., Chighizola, Cecilia B., Luigi Meroni, Pier, Coghlan, Gerry, Newton, Florence, Derrett-Smith, Emma C., Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, MacAllister, Raymond, Futema, Marta, Pantelidis, Panagiotis, Renzoni, Elizabeth, Schreiber, Benjamin E., Coghlan, Gerry J., Wells, Athol U., Welsh, Ken, Fonseca, Carmen, Ponticos, Markella, Wells, Athol, Guillevin, Loic, Schwierin, Barbara, Rosenberg, Daniel, Silkey, Mariabeth, Parapuram, Sunil, Shi-wen, Xu, Denton, Christopher, Ahmed Abdi, Bahja, Xu, Shiwen, Nihtyanova, Svetlana, Ong, Voon, Black, Carol, Denton, Chris, Lutalo, Pamela, Shattles, Warren, Jones, Hugh, Nouri, Reem, Hepburn, Alastair, Chard, Michael, Horwood, Natalie, Lynn, Myo, Duke, Oliver, Kiely, Patrick, Zouita, Louisa, Davies, Ursula, Hughes, Rod, Lloyd, Mark, Nikitorowicz Buniak, Joanna, Shiwen, Xu, Abraham, David, Stratton, Richard, Hügle, Thomas, Schuetz, Philipp, Daikeler, Thomas, Tyndall, Alan, Matucci-Cerinic, Marco, Walker, Ulrich A., van Laar, Jacob M., Pauling, John D., Flower, Victoria, McHugh, Neil, Liu, Shangxi, Leask, Andrew, Aden, Nima, Khan, Korsa, Hoyles, Rachel, Bhagat, Shweta, Drummond, Tom, Goh, Cyndi, Busch, Robert, Hall, Frances, Meyer, Paul, Moinzadeh, Pia, Krieg, Thomas, Hellmich, Martin, Brinckmann, Juergen, Neumann, Elena, Mueller-Ladner, Ulf, Kreuter, Alexander, Dumitresco, Daniel, Rosenkranz, Stefan, Hunzelmann, Nicolas, Binai, Nadine, Huegle, Thomas, van Laar, Jaap, Sonnylal, S., Tam, A., Jones, H., Leask, A., Norman, J., Denton, C., de Crombrugghe, B., Abraham, D., Chighizola, Cecilia B., Luigi Meroni, Pier, Coghlan, Gerry, Newton, Florence, Derrett-Smith, Emma C., Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, MacAllister, Raymond, Futema, Marta, Pantelidis, Panagiotis, Renzoni, Elizabeth, Schreiber, Benjamin E., Coghlan, Gerry J., Wells, Athol U., Welsh, Ken, Fonseca, Carmen, Ponticos, Markella, Wells, Athol, Guillevin, Loic, Schwierin, Barbara, Rosenberg, Daniel, Silkey, Mariabeth, Parapuram, Sunil, Shi-wen, Xu, Denton, Christopher, Ahmed Abdi, Bahja, and Xu, Shiwen

Abstract

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years. Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice. Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003). During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4%

Published
2017

23. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor.

Author

Liakouli, Vasiliki, Elies, Jacobo, El-Sherbiny, Yasser Mohamed, Scarcia, Margherita, Grant, Gary, Abignano, Giuseppina, Derrett-Smith, Emma C., Esteves, Filomena, Cipriani, Paola, Emery, Paul, Denton, Christopher P., Giacomelli, Roberto, Mavria, Georgia, Del Galdo, Francesco, and Elies Comez, Jacobo

Subjects
PROTEIN metabolism, ANIMAL experimentation, CARRIER proteins, CELL culture, COMPARATIVE studies, EPITHELIAL cells, FIBROBLASTS, GROWTH factors, IMMUNOHISTOCHEMISTRY, RESEARCH methodology, MEDICAL cooperation, MICE, NERVE growth factor, POLYMERASE chain reaction, RESEARCH, SKIN, SYSTEMIC scleroderma, EVALUATION research, PATHOLOGIC neovascularization, METABOLISM
Abstract

Objectives: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis.Methods: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast-endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis.Results: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density.Conclusions: Our data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc. [ABSTRACT FROM AUTHOR]

Published
2018
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26. Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort

Author

Nihtyanova, Svetlana, Ong, Voon, Black, Carol, Denton, Chris, Lutalo, Pamela, Shattles, Warren, Jones, Hugh, Nouri, Reem, Hepburn, Alastair, Chard, Michael, Horwood, Natalie, Lynn, Myo, Duke, Oliver, Kiely, Patrick, Zouita, Louisa, Davies, Ursula, Hughes, Rod, Lloyd, Mark, Nikitorowicz Buniak, Joanna, Shiwen, Xu, Abraham, David, Stratton, Richard, Hügle, Thomas, Schuetz, Philipp, Daikeler, Thomas, Tyndall, Alan, Matucci-Cerinic, Marco, Walker, Ulrich A., van Laar, Jacob M., Pauling, John D., Flower, Victoria, McHugh, Neil, Liu, Shangxi, Leask, Andrew, Aden, Nima, Khan, Korsa, Hoyles, Rachel, Bhagat, Shweta, Drummond, Tom, Goh, Cyndi, Busch, Robert, Hall, Frances, Meyer, Paul, Moinzadeh, Pia, Krieg, Thomas, Hellmich, Martin, Brinckmann, Juergen, Neumann, Elena, Mueller-Ladner, Ulf, Kreuter, Alexander, Dumitresco, Daniel, Rosenkranz, Stefan, Hunzelmann, Nicolas, Binai, Nadine, Huegle, Thomas, van Laar, Jaap, Sonnylal, S., Tam, A., Jones, H., Leask, A., Norman, J., Denton, C., de Crombrugghe, B., Abraham, D., Chighizola, Cecilia B., Luigi Meroni, Pier, Coghlan, Gerry, Newton, Florence, Derrett-Smith, Emma C., Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, MacAllister, Raymond, Futema, Marta, Pantelidis, Panagiotis, Renzoni, Elizabeth, Schreiber, Benjamin E., Coghlan, Gerry J., Wells, Athol U., Welsh, Ken, Fonseca, Carmen, Ponticos, Markella, Wells, Athol, Guillevin, Loic, Schwierin, Barbara, Rosenberg, Daniel, Silkey, Mariabeth, Parapuram, Sunil, Shi-wen, Xu, Denton, Christopher, Ahmed Abdi, Bahja, Xu, Shiwen, Nihtyanova, Svetlana, Ong, Voon, Black, Carol, Denton, Chris, Lutalo, Pamela, Shattles, Warren, Jones, Hugh, Nouri, Reem, Hepburn, Alastair, Chard, Michael, Horwood, Natalie, Lynn, Myo, Duke, Oliver, Kiely, Patrick, Zouita, Louisa, Davies, Ursula, Hughes, Rod, Lloyd, Mark, Nikitorowicz Buniak, Joanna, Shiwen, Xu, Abraham, David, Stratton, Richard, Hügle, Thomas, Schuetz, Philipp, Daikeler, Thomas, Tyndall, Alan, Matucci-Cerinic, Marco, Walker, Ulrich A., van Laar, Jacob M., Pauling, John D., Flower, Victoria, McHugh, Neil, Liu, Shangxi, Leask, Andrew, Aden, Nima, Khan, Korsa, Hoyles, Rachel, Bhagat, Shweta, Drummond, Tom, Goh, Cyndi, Busch, Robert, Hall, Frances, Meyer, Paul, Moinzadeh, Pia, Krieg, Thomas, Hellmich, Martin, Brinckmann, Juergen, Neumann, Elena, Mueller-Ladner, Ulf, Kreuter, Alexander, Dumitresco, Daniel, Rosenkranz, Stefan, Hunzelmann, Nicolas, Binai, Nadine, Huegle, Thomas, van Laar, Jaap, Sonnylal, S., Tam, A., Jones, H., Leask, A., Norman, J., Denton, C., de Crombrugghe, B., Abraham, D., Chighizola, Cecilia B., Luigi Meroni, Pier, Coghlan, Gerry, Newton, Florence, Derrett-Smith, Emma C., Dooley, Audrey, Baliga, Reshma, Hobbs, Adrian, MacAllister, Raymond, Futema, Marta, Pantelidis, Panagiotis, Renzoni, Elizabeth, Schreiber, Benjamin E., Coghlan, Gerry J., Wells, Athol U., Welsh, Ken, Fonseca, Carmen, Ponticos, Markella, Wells, Athol, Guillevin, Loic, Schwierin, Barbara, Rosenberg, Daniel, Silkey, Mariabeth, Parapuram, Sunil, Shi-wen, Xu, Denton, Christopher, Ahmed Abdi, Bahja, and Xu, Shiwen

Abstract

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years. Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice. Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003). During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4%

27. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

Author

Gary Grant, Christopher P. Denton, Francesco Del Galdo, Georgia Mavria, Roberto Giacomelli, Giuseppina Abignano, Vasiliki Liakouli, Paola Cipriani, Filomena Esteves, Margherita Scarcia, Jacobo Elies, Yasser M. El-Sherbiny, Paul Emery, Emma Derrett-Smith, Liakouli, Vasiliki, Elies, Jacobo, El-Sherbiny, Yasser Mohamed, Scarcia, Margherita, Grant, Gary, Abignano, Giuseppina, Derrett-Smith, Emma C, Esteves, Filomena, Cipriani, Paola, Emery, Paul, Denton, Christopher P, Giacomelli, Roberto, Mavria, Georgia, and Del Galdo, Francesco

Subjects
0301 basic medicine, Male, Angiogenesis, systemic sclerosis, Caveolin 1, fibroblast, Mice, 0302 clinical medicine, Transforming Growth Factor beta, autoimmune diseases, fibroblasts, Immunology and Allergy, Basic and Translational Research, Cells, Cultured, Skin, biology, integumentary system, Neovascularization, Pathologic, Immunohistochemistry, medicine.anatomical_structure, cardiovascular system, Female, Myofibroblast, Immunology, autoimmune disease, Mice, Transgenic, Real-Time Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, PEDF, Rheumatology, medicine, Animals, Humans, Nerve Growth Factors, Fibroblast, Eye Proteins, Serpins, 030203 arthritis & rheumatology, Matrigel, Scleroderma, Systemic, business.industry, Endothelial Cells, Transforming growth factor beta, Fibroblasts, 030104 developmental biology, Cancer research, biology.protein, business, Transforming growth factor
Abstract

ObjectivesSystemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis.MethodsPEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast–endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis.ResultsPEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density.ConclusionsOur data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc.

Published
2017

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