title: Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome.
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-beta 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-beta mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-beta 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 TGFbeta- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-beta and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.
authors.affiliation: Rheumatology Section, The Arthritis Center, Boston University School of Medicine, 72 E Newton Street, Boston, MA 02218, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lemaire
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Farina
authors.forename: Julie
authors.initials: J
authors.lastname: Bayle
authors.forename: Michael
authors.initials: M
authors.lastname: Dimarzio
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.forename: Ausra
authors.initials: A
authors.lastname: Milano
authors.forename: Bernard
authors.initials: B
authors.lastname: Perbal
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D000818:Animals; D001706:Biopsy; D055511:CCN Intercellular Signaling Proteins; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008382:Marfan Syndrome / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054392:Adipokines
chemical_list: D055511:CCN Intercellular Signaling Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D055514:Nephroblastoma Overexpressed Protein; D011518:Proto-Oncogene Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C116396:CCN4 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse