A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis
CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models...
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| Veröffentlicht in: | Experimental dermatology 2015-02, Vol.24 (2), p.127-132 |
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| creator | Saigusa, Ryosuke Asano, Yoshihide Taniguchi, Takashi Yamashita, Takashi Takahashi, Takehiro Ichimura, Yohei Toyama, Tetsuo Tamaki, Zenshiro Tada, Yayoi Sugaya, Makoto Kadono, Takafumi Sato, Shinichi |
| description | CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1+/− mice and partially in those of endothelial cell‐specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc. |
| doi_str_mv | 10.1111/exd.12602 |
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To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1+/− mice and partially in those of endothelial cell‐specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.</description><identifier>ISSN: 0906-6705</identifier><identifier>EISSN: 1600-0625</identifier><identifier>DOI: 10.1111/exd.12602</identifier><identifier>PMID: 25421497</identifier><language>eng</language><publisher>Denmark: Blackwell Publishing Ltd</publisher><subject>Aged ; angiogenesis ; Animals ; Blood Vessels - metabolism ; Blood Vessels - physiopathology ; CCN1 ; Cysteine-Rich Protein 61 - blood ; Cysteine-Rich Protein 61 - metabolism ; digital ulcers ; Endothelium - metabolism ; Epigenesis, Genetic ; Female ; Fibroblasts - metabolism ; Fingers - physiopathology ; Gene Silencing ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Neovascularization, Pathologic ; Proto-Oncogene Protein c-fli-1 - deficiency ; Proto-Oncogene Protein c-fli-1 - genetics ; Scleroderma, Systemic - metabolism ; Skin - blood supply ; Skin - metabolism ; Skin Ulcer - metabolism ; systemic sclerosis ; vasculogenesis</subject><ispartof>Experimental dermatology, 2015-02, Vol.24 (2), p.127-132</ispartof><rights>2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fexd.12602$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fexd.12602$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25421497$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saigusa, Ryosuke</creatorcontrib><creatorcontrib>Asano, Yoshihide</creatorcontrib><creatorcontrib>Taniguchi, Takashi</creatorcontrib><creatorcontrib>Yamashita, Takashi</creatorcontrib><creatorcontrib>Takahashi, Takehiro</creatorcontrib><creatorcontrib>Ichimura, Yohei</creatorcontrib><creatorcontrib>Toyama, Tetsuo</creatorcontrib><creatorcontrib>Tamaki, Zenshiro</creatorcontrib><creatorcontrib>Tada, Yayoi</creatorcontrib><creatorcontrib>Sugaya, Makoto</creatorcontrib><creatorcontrib>Kadono, Takafumi</creatorcontrib><creatorcontrib>Sato, Shinichi</creatorcontrib><title>A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis</title><title>Experimental dermatology</title><addtitle>Exp Dermatol</addtitle><description>CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1+/− mice and partially in those of endothelial cell‐specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.</description><subject>Aged</subject><subject>angiogenesis</subject><subject>Animals</subject><subject>Blood Vessels - metabolism</subject><subject>Blood Vessels - physiopathology</subject><subject>CCN1</subject><subject>Cysteine-Rich Protein 61 - blood</subject><subject>Cysteine-Rich Protein 61 - metabolism</subject><subject>digital ulcers</subject><subject>Endothelium - metabolism</subject><subject>Epigenesis, Genetic</subject><subject>Female</subject><subject>Fibroblasts - metabolism</subject><subject>Fingers - physiopathology</subject><subject>Gene Silencing</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Neovascularization, Pathologic</subject><subject>Proto-Oncogene Protein c-fli-1 - deficiency</subject><subject>Proto-Oncogene Protein c-fli-1 - genetics</subject><subject>Scleroderma, Systemic - metabolism</subject><subject>Skin - blood supply</subject><subject>Skin - metabolism</subject><subject>Skin Ulcer - metabolism</subject><subject>systemic sclerosis</subject><subject>vasculogenesis</subject><issn>0906-6705</issn><issn>1600-0625</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kcFO3DAQhi1UBAv00BeofOwlYDu20xzRFtgiRKUKKDfLsSd0Wide4gTYd-hD492l-DLWzPf_0sxPyCfOjnl-J_Dij7nQTOyQGdeMFUwL9YHMWM10oSum9slBSn8Y41VZqT2yL5QUXNbVjPw7pcuYEjYBqIv9OGAzjRh7GlsKvY_jbwhoA53Przn18bkf4GEKdoP4CegY6XnAPIIWHULvVutWVuXOE4S47KAf12YeH3DMRlNwMCSKPU2rNEKHjiYXYIgJ0xHZbW1I8PGtHpLb87Ob-aK4-nHxfX56VWCplCisFr6tvHV5IcZcXavSts5WYIVnTNS2KZ1lum20BtGopqytlF89OC0Vb6UuD8mXre9yiI8TpNF0mByEYHuIUzJcKyGFKGWV0c9v6NR04M1ywM4OK_P_ghk42QLPGGD1PufMrKMxORqzicac3X_bfLKi2Cow7__yrrDDX6PX-Zhf1xdmcSnv734uFuayfAVlZZJe</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Saigusa, Ryosuke</creator><creator>Asano, Yoshihide</creator><creator>Taniguchi, Takashi</creator><creator>Yamashita, Takashi</creator><creator>Takahashi, Takehiro</creator><creator>Ichimura, Yohei</creator><creator>Toyama, Tetsuo</creator><creator>Tamaki, Zenshiro</creator><creator>Tada, Yayoi</creator><creator>Sugaya, Makoto</creator><creator>Kadono, Takafumi</creator><creator>Sato, Shinichi</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201502</creationdate><title>A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis</title><author>Saigusa, Ryosuke ; Asano, Yoshihide ; Taniguchi, Takashi ; Yamashita, Takashi ; Takahashi, Takehiro ; Ichimura, Yohei ; Toyama, Tetsuo ; Tamaki, Zenshiro ; Tada, Yayoi ; Sugaya, Makoto ; Kadono, Takafumi ; Sato, Shinichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i3552-a62df7dac00100c9953afca7ea2d0029ab3ca06fb66e2b5b39a448dec6451f463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>angiogenesis</topic><topic>Animals</topic><topic>Blood Vessels - metabolism</topic><topic>Blood Vessels - physiopathology</topic><topic>CCN1</topic><topic>Cysteine-Rich Protein 61 - blood</topic><topic>Cysteine-Rich Protein 61 - metabolism</topic><topic>digital ulcers</topic><topic>Endothelium - metabolism</topic><topic>Epigenesis, Genetic</topic><topic>Female</topic><topic>Fibroblasts - metabolism</topic><topic>Fingers - physiopathology</topic><topic>Gene Silencing</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Middle Aged</topic><topic>Neovascularization, Pathologic</topic><topic>Proto-Oncogene Protein c-fli-1 - deficiency</topic><topic>Proto-Oncogene Protein c-fli-1 - genetics</topic><topic>Scleroderma, Systemic - metabolism</topic><topic>Skin - blood supply</topic><topic>Skin - metabolism</topic><topic>Skin Ulcer - metabolism</topic><topic>systemic sclerosis</topic><topic>vasculogenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saigusa, Ryosuke</creatorcontrib><creatorcontrib>Asano, Yoshihide</creatorcontrib><creatorcontrib>Taniguchi, Takashi</creatorcontrib><creatorcontrib>Yamashita, Takashi</creatorcontrib><creatorcontrib>Takahashi, Takehiro</creatorcontrib><creatorcontrib>Ichimura, Yohei</creatorcontrib><creatorcontrib>Toyama, Tetsuo</creatorcontrib><creatorcontrib>Tamaki, Zenshiro</creatorcontrib><creatorcontrib>Tada, Yayoi</creatorcontrib><creatorcontrib>Sugaya, Makoto</creatorcontrib><creatorcontrib>Kadono, Takafumi</creatorcontrib><creatorcontrib>Sato, Shinichi</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental dermatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saigusa, Ryosuke</au><au>Asano, Yoshihide</au><au>Taniguchi, Takashi</au><au>Yamashita, Takashi</au><au>Takahashi, Takehiro</au><au>Ichimura, Yohei</au><au>Toyama, Tetsuo</au><au>Tamaki, Zenshiro</au><au>Tada, Yayoi</au><au>Sugaya, Makoto</au><au>Kadono, Takafumi</au><au>Sato, Shinichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis</atitle><jtitle>Experimental dermatology</jtitle><addtitle>Exp Dermatol</addtitle><date>2015-02</date><risdate>2015</risdate><volume>24</volume><issue>2</issue><spage>127</spage><epage>132</epage><pages>127-132</pages><issn>0906-6705</issn><eissn>1600-0625</eissn><abstract>CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1+/− mice and partially in those of endothelial cell‐specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.</abstract><cop>Denmark</cop><pub>Blackwell Publishing Ltd</pub><pmid>25421497</pmid><doi>10.1111/exd.12602</doi><tpages>6</tpages></addata></record> |
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| subjects | Aged angiogenesis Animals Blood Vessels - metabolism Blood Vessels - physiopathology CCN1 Cysteine-Rich Protein 61 - blood Cysteine-Rich Protein 61 - metabolism digital ulcers Endothelium - metabolism Epigenesis, Genetic Female Fibroblasts - metabolism Fingers - physiopathology Gene Silencing Humans Immunohistochemistry Male Mice Mice, Knockout Middle Aged Neovascularization, Pathologic Proto-Oncogene Protein c-fli-1 - deficiency Proto-Oncogene Protein c-fli-1 - genetics Scleroderma, Systemic - metabolism Skin - blood supply Skin - metabolism Skin Ulcer - metabolism systemic sclerosis vasculogenesis |
| title | A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis |
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