Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-β- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome
Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-β and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3...
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| Veröffentlicht in: | Journal of investigative dermatology 2010-06, Vol.130 (6), p.1514-1523 |
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| creator | Lemaire, Raphael Farina, Giuseppina Bayle, Julie Dimarzio, Michael Pendergrass, Sarah A. Milano, Ausra Whitfield, Michael L. Lafyatis, Robert |
| description | Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-β and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-β mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-β and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFβ- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-β and Wnt for fibrillin fibrillogenesis and profibrotic gene expression. |
| doi_str_mv | 10.1038/jid.2010.15 |
| format | Article |
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We have previously shown that TGF-β and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-β mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-β and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFβ- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-β and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.</description><identifier>ISSN: 0022-202X</identifier><identifier>EISSN: 1523-1747</identifier><identifier>DOI: 10.1038/jid.2010.15</identifier><identifier>PMID: 20182440</identifier><identifier>CODEN: JIDEAE</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Biopsy ; Case-Control Studies ; CCN Intercellular Signaling Proteins ; Cells, Cultured ; Dermatology ; Disease Models, Animal ; Fibrillin-1 ; Fibrillins ; Humans ; Intracellular Signaling Peptides and Proteins - metabolism ; Marfan Syndrome - metabolism ; Marfan Syndrome - pathology ; Medical sciences ; Mice ; Mice, Mutant Strains ; Microfilament Proteins - antagonists & inhibitors ; Microfilament Proteins - metabolism ; Nephroblastoma Overexpressed Protein - metabolism ; Proto-Oncogene Proteins - metabolism ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; Scleroderma, Systemic - metabolism ; Scleroderma, Systemic - pathology ; Signal Transduction - physiology ; Skin - metabolism ; Skin - pathology ; Smad3 Protein - metabolism ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - metabolism ; Wnt Proteins - antagonists & inhibitors ; Wnt Proteins - metabolism</subject><ispartof>Journal of investigative dermatology, 2010-06, Vol.130 (6), p.1514-1523</ispartof><rights>2010 The Society for Investigative Dermatology, Inc</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-51a80c52f1de40092c30b75b773af1b7b83e8238355247776be4702bad7718713</citedby><cites>FETCH-LOGICAL-c480t-51a80c52f1de40092c30b75b773af1b7b83e8238355247776be4702bad7718713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27928,27929,64391</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22835392$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20182440$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lemaire, Raphael</creatorcontrib><creatorcontrib>Farina, Giuseppina</creatorcontrib><creatorcontrib>Bayle, Julie</creatorcontrib><creatorcontrib>Dimarzio, Michael</creatorcontrib><creatorcontrib>Pendergrass, Sarah A.</creatorcontrib><creatorcontrib>Milano, Ausra</creatorcontrib><creatorcontrib>Whitfield, Michael L.</creatorcontrib><creatorcontrib>Lafyatis, Robert</creatorcontrib><title>Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-β- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome</title><title>Journal of investigative dermatology</title><addtitle>J Invest Dermatol</addtitle><description>Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-β and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-β mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-β and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFβ- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-β and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biopsy</subject><subject>Case-Control Studies</subject><subject>CCN Intercellular Signaling Proteins</subject><subject>Cells, Cultured</subject><subject>Dermatology</subject><subject>Disease Models, Animal</subject><subject>Fibrillin-1</subject><subject>Fibrillins</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Marfan Syndrome - metabolism</subject><subject>Marfan Syndrome - pathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Microfilament Proteins - antagonists & inhibitors</subject><subject>Microfilament Proteins - metabolism</subject><subject>Nephroblastoma Overexpressed Protein - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>Scleroderma, Systemic - metabolism</subject><subject>Scleroderma, Systemic - pathology</subject><subject>Signal Transduction - physiology</subject><subject>Skin - metabolism</subject><subject>Skin - pathology</subject><subject>Smad3 Protein - metabolism</subject><subject>Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Wnt Proteins - antagonists & inhibitors</subject><subject>Wnt Proteins - metabolism</subject><issn>0022-202X</issn><issn>1523-1747</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptks9uEzEQxi0EoqFw4g6-IA5oi_-sY_eCVEVNQWoAKUVws7ze2a2rjV1sb6U-Ce_RB-kz4SUhgIQvlj2_mW_GnxF6TskRJVy9vXLtESPTSTxAMyoYr6is5UM0I4SxihH27QA9SemKEDqvhXqMDgquWF2TGfpx4rPpg3cpO4tPuw5sxqHD-RLwyuToLAzDOJiI1673ZnC-x59jyOA8Xiw-chw8vjhbVvd3FTa-xV99rlbQOpOhxUvXRDeUnNCDh-QSLlnr25RhU8TWdoAYptspcWViZ6aob2PYwFP0qDNDgme7_RB9WZ5eLN5X55_OPixOzitbK5IrQY0iVrCOtlATcswsJ40UjZTcdLSRjeKgGFdcCFZLKecN1JKwxrRSUiUpP0TvtnWvx2YDrQWfoxn0dXQbE291ME7_G_HuUvfhRnMiaS1FKfB6VyCG7yOkrDcuTY9mPIQxacnLmgtVF_LNlrRl6hSh26tQoicndXFST05qOtV98Xdje_a3dQV4tQNMsmboovHWpT8cK0PzY1a4l1vOmzxG2ANFbNL6JSW2BJSHvnEQdbIOvC02xvIddBvcf1v8CTWFxVk</recordid><startdate>20100601</startdate><enddate>20100601</enddate><creator>Lemaire, Raphael</creator><creator>Farina, Giuseppina</creator><creator>Bayle, Julie</creator><creator>Dimarzio, Michael</creator><creator>Pendergrass, Sarah A.</creator><creator>Milano, Ausra</creator><creator>Whitfield, Michael L.</creator><creator>Lafyatis, Robert</creator><general>Elsevier Inc</general><general>Nature Publishing Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100601</creationdate><title>Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-β- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome</title><author>Lemaire, Raphael ; Farina, Giuseppina ; Bayle, Julie ; Dimarzio, Michael ; Pendergrass, Sarah A. ; Milano, Ausra ; Whitfield, Michael L. ; Lafyatis, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c480t-51a80c52f1de40092c30b75b773af1b7b83e8238355247776be4702bad7718713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biopsy</topic><topic>Case-Control Studies</topic><topic>CCN Intercellular Signaling Proteins</topic><topic>Cells, Cultured</topic><topic>Dermatology</topic><topic>Disease Models, Animal</topic><topic>Fibrillin-1</topic><topic>Fibrillins</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Marfan Syndrome - metabolism</topic><topic>Marfan Syndrome - pathology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Microfilament Proteins - antagonists & inhibitors</topic><topic>Microfilament Proteins - metabolism</topic><topic>Nephroblastoma Overexpressed Protein - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>Scleroderma, Systemic - metabolism</topic><topic>Scleroderma, Systemic - pathology</topic><topic>Signal Transduction - physiology</topic><topic>Skin - metabolism</topic><topic>Skin - pathology</topic><topic>Smad3 Protein - metabolism</topic><topic>Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Wnt Proteins - antagonists & inhibitors</topic><topic>Wnt Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lemaire, Raphael</creatorcontrib><creatorcontrib>Farina, Giuseppina</creatorcontrib><creatorcontrib>Bayle, Julie</creatorcontrib><creatorcontrib>Dimarzio, Michael</creatorcontrib><creatorcontrib>Pendergrass, Sarah A.</creatorcontrib><creatorcontrib>Milano, Ausra</creatorcontrib><creatorcontrib>Whitfield, Michael L.</creatorcontrib><creatorcontrib>Lafyatis, Robert</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of investigative dermatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lemaire, Raphael</au><au>Farina, Giuseppina</au><au>Bayle, Julie</au><au>Dimarzio, Michael</au><au>Pendergrass, Sarah A.</au><au>Milano, Ausra</au><au>Whitfield, Michael L.</au><au>Lafyatis, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-β- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome</atitle><jtitle>Journal of investigative dermatology</jtitle><addtitle>J Invest Dermatol</addtitle><date>2010-06-01</date><risdate>2010</risdate><volume>130</volume><issue>6</issue><spage>1514</spage><epage>1523</epage><pages>1514-1523</pages><issn>0022-202X</issn><eissn>1523-1747</eissn><coden>JIDEAE</coden><abstract>Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-β and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-β mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-β and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFβ- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-β and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>20182440</pmid><doi>10.1038/jid.2010.15</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of investigative dermatology, 2010-06, Vol.130 (6), p.1514-1523 |
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| subjects | Animals Biological and medical sciences Biopsy Case-Control Studies CCN Intercellular Signaling Proteins Cells, Cultured Dermatology Disease Models, Animal Fibrillin-1 Fibrillins Humans Intracellular Signaling Peptides and Proteins - metabolism Marfan Syndrome - metabolism Marfan Syndrome - pathology Medical sciences Mice Mice, Mutant Strains Microfilament Proteins - antagonists & inhibitors Microfilament Proteins - metabolism Nephroblastoma Overexpressed Protein - metabolism Proto-Oncogene Proteins - metabolism Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis Scleroderma, Systemic - metabolism Scleroderma, Systemic - pathology Signal Transduction - physiology Skin - metabolism Skin - pathology Smad3 Protein - metabolism Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - metabolism Wnt Proteins - antagonists & inhibitors Wnt Proteins - metabolism |
| title | Antagonistic Effect of the Matricellular Signaling Protein CCN3 on TGF-β- and Wnt-Mediated Fibrillinogenesis in Systemic Sclerosis and Marfan Syndrome |
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