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Could Aging Human Skin Use a Connective Tissue Growth Factor

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Could Aging Human Skin Use a Connective Tissue Growth Factor View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector COMMENTARY pattern in human ridged skin as an Vassar R, Coulombe PA, Degenstein L et al. (1991) localization for CTGF, TGF-β, and adaptation to high physical stress. Br J Mutant keratin expression in transgenic mice type I procollagen-α1, as well as Dermatol 139:767–75 causes marked abnormalities resembling a human genetic skin disease. Cell 64:365–80 CTGF’s effects on TGF-β signaling. Takahashi K, Paladini RD, Coulombe PA (1995) Using samples of young (21–30 years Cloning and characterization of multiple Wilson NJ, Messenger AG, Leachman SA et al. human genes and cDNAs encoding highly (2010) Keratin K6c mutations cause focal of age) and aged (80 or more years related type 2 keratin 6 isoforms. J Biol palmoplantar keratoderma. J Invest Dermatol of age) but otherwise normal human Chem 270:18581–92 130:425–9 skin, and laser-capture microdissect- ed cells, the authors show that TGF-β and CTGF are normally expressed and produced in skin and skin fibroblasts. See related article on pg 415 Comparing samples from young and aged subjects, Quan et al. found that Could Aging Human Skin Use a in aged skin and fibroblasts, TGF-β, CTGF, and type I procollagen mRNA Connective Tissue Growth Factor and protein levels were coordinately reduced. Using transfected normal human dermal fibroblasts, knock- Boost to Increase Collagen Content? down of CTGF was associated with Noelynn Oliver1, Mark Sternlicht1, Karin Gerritsen2 decreased type I procollagen promoter and Roel Goldschmeding1,2 activity (COL1A2), mRNA, and pro- tein content, whereas overexpression The roles of connective tissue growth factor (CTGF) and transforming growth of V5-tagged human CTGF increased factor-β (TGF-β), both well-known collagen production stimulators, were the same readouts. Three approaches examined in skin aging. Aged skin and fibroblasts exhibited a coordinate to block signaling due to endogenous decrease in CTGF, TGF-β, and type I procollagen expression and content. CTGF TGF-β were used to assess molecular knockdown and TGF-β blockade in normal dermal fibroblasts reduced procol- mechanisms by which CTGF modu- lagen expression, whereas overexpressing CTGF increased procollagen by a lates type I procollagen: (i) a specific TGF-β/Smad signaling–dependent mechanism without involving Smad2/3. TGF-βRI kinase inhibitor SB431542, Journal of Investigative Dermatology (2010) 130, 338–341. doi:10.1038/jid.2009.331 (ii) Smad4 knockdown, and (iii) over- expression of inhibitory Smad7. All approaches completely blocked the Background reported disease associations (Leask CTGF-mediated increase in type I pro- Type I collagen is a major struc- et al., 2009; Cicha et al., 2009), collagen expression and production, tural protein in human skin and, by potential macromolecular interac- indicating that TGF-β receptor and mass, the most abundant protein in tions, and complex gene regulation Smad signaling are required. However, the human body. The association of that also involves disease-associated no effects of CTGF knockdown or over- age-dependent collagen loss with processes and factors (Figure 1). The expression were observed on TGF-β- thinning and fragility of elderly skin evolution of a purely pathogenic fac- dependent Smad2/3 phosphorylation has long been appreciated, yet the tor is unlikely without invoking an or Smad3 transcriptional activity. underlying mechanisms are not well extreme selfish-gene concept, and the On the basis of these findings, the understood. A recent study (Quan results of Quan et al., which address authors conclude that endogenous et al., 2010, this issue) suggests that CTGF function in normal young and production of both TGF-β and CTGF diminished expression of connective aging skin, provide an alternative in human dermal fibroblasts normally tissue growth factor (CTGF), together view of CTGF’s physiological signifi- acts to modulate type I procollagen with diminished transforming growth cance in tissue homeostasis. expression in skin. They propose that factor (TGF)-β/Smad signaling, is this involves a TGF-β/Smad/CTGF responsible for this progressive loss of CTGF in aging skin: new findings axis that is operated by interdepen- dermal collagen. CTGF is a secreted, By means of associative and mecha- dent, yet distinct, mechanisms to matri cellular protein, and, like that nistic in vivo and in vitro studies, regulate type I procollagen produc- of other such proteins, its function is Quan et al. (2010) probe the impor- tion. Decreased expression of TGF-β thought to be regulatory, not struc- tance of CTGF and TGF-β for col- and CTGF by aged skin fibroblasts is tural. CTGF is generally considered a lagen loss in aging skin. They report proposed to underlie age-associated pathogenic factor because of its many findings on expression, content, and downregulation of the TGF-β/Smad/ CTGF axis, thereby leading to reduced type I procollagen expression. These 1Therapeutics Research, FibroGen, Inc., San Francisco, California, USA and 2Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands results suggest beneficial effects of Correspondence: Noelynn Oliver, FibroGen, Inc., 409 Illinois Street, San Francisco, California 94080, USA. CTGF and provide novel insight into E-mail: [email protected] the mechanisms of skin aging. 338 Journal of Investigative Dermatology (2010), Volume 130 COMMENTARY TGF-β Complexity of CTGF action: binding Angiotensin II CAATbox partners, metabolism, and expression VEGF ? CAESAR CTGF is a modular protein composed Sp1 of four domains that have homol- TNF-α Ets1 CTGF gene E5 Nitric oxide 3′ UTR ogy with certain protein motifs. Each TATA E1 CTGF domain has been reported to SMADs BCE-1 E2 E4 35 kDa interact with biologically active fac- E3 mRNA NF- B stabilizilizer tors and binding partners to regulate HIF-1 their effects (Figure 2). Of note, in AP1 HRE 5.2 Sp3 HRE 5.1 lung epithelial cells CTGF has been Aldosterone, (mouse) (mouse) mechanical reported to enhance binding of TGF-β ? Polymorphic stress C/EBP Sp1/Sp3 site with TGF-β receptor complex, there- ? Glucocorticoids by increasing Smad2 phosphorylation Hypoxia Endothelin-1 and Smad-dependent gene transcrip- Bradykinin Thrombin, factor Xa, factor VIIa, high glucose, tion (Abreu et al., 2002). However, advanced glycation end products Quan et al. (2010) demonstrate that, although CTGF knockdown or over- expression affected type I procolla- Figure 1. CTGF gene regulation is complex. The human connective tissue growth factor (CTGF) gen expression in a TGF-β-dependent promoter contains multiple control elements that are regulated by a variety of inducing factors (green manner, it did not alter Smad2/3 arrows), inhibitory factors (red dashed lines), and mechanical forces or hypoxic stimuli. Many of these phosphorylation and had no effect regulators are disease associated. CTGF gene transcription is strongly induced by transforming growth on TGF-β/Smad3-dependent reporter factor-β (TGF-β) and also by angiotensin II, endothelin-1, and advanced glycation end products, at gene transcription. This observation least partially through TGF-β and SMAD-independent pathways. Posttranscriptional control elements (CAESAR, cis-acting element of structure-anchored repression) and a functional, scleroderma-associated is concordant with an independent polymorphism (Sp1/Sp3 site) have also been observed. BCE, basal control element; E1–E5, exons 1–5; observation (Pannu et al., 2007) that HRE, hypoxia-responsive element; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; TGF-β-dependent type 1 procollagen TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor. production is mediated by Alk1/ Smad1 and ERK1/2, but not Smad 2/3, in normal dermal fibroblasts. Together, these data do not support a simple model of CTGF regulating type I pro- Relationship of CTGF’s physiologic received little attention compared collagen expression through direct and pathogenic functions with the extensive literature on the augmentation of the TGF-β/Smad2/3 The relationship of CTGF’s patho- role and association of CTGF in dis- pathway and are consistent with the physiologic actions to its normal ease states involving fibrosis and, idea that different mechanisms oper- physiological functions is unknown; more recently, cancer (Leask et al., ate in human dermal fibroblasts and therefore, a better understanding of 2009; Cicha and Goppelt-Struebe, lung epithelial cells. The CTGF– CTGF’s biological significance for 2009; Abraham, 2008). To summa- vascular endothelial growth factor normal and aging skin will be gained rize, CTGF expression and protein (VEGF) relationship and its impact by collecting mechanistic informa- are elevated in nearly all fibrotic tis- on angiogenesis further exemplify tion on both activities. CTGF is essen- sues examined. Exceptions appear to the potential complexity and con- tial in embryonic development, in involve inactive disease processes in text dependence of CTGF action. In which it is important for normal car- which affected tissue has progressed this case, over and above all the pos- tilage and bone formation. In adults, to inert scar tissue. Increased CTGF sible physical interactions, CTGF and however, normal physiologic CTGF concentrations in blood and other bio- VEGF can each induce expression of levels appear dispensable because logical fluids have also been reported the other. Cicha and Goppelt-Struebe, animal studies testing CTGF block- for many fibrotic diseases. As a result, (2009) give an excellent review of ade via CTGF antisense or anti-CTGF there is active interest in CTGF’s util- CTGF and angiogenesis, detailing antibody have not reported adverse ity as a diagnostic and prognostic bio- evidence for pro-, anti-, and neutral effects (Guha et al., 2007; Ponticos marker (Abraham, 2008; Leask et al., effects of CTGF and emphasizing et al., 2009), and mice carrying a 2009; Gressner and Gressner, 2009). that microenvironment strongly influ- single functional CTGF allele exhibit Associations between CTGF and can- ences outcome. Because translation no obvious phenotype.
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