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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1483-1489.)
© 1997 American Heart Association, Inc.

Articles

Connective Tissue Growth Factor

Friend or Foe?

Barry S. Oemar; ; Thomas F. Lüscher

From the Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, and Cardiology, University Hospital Zürich, Switzerland.

Correspondence to Barry S. Oemar, MD, Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail oemar{at}ubaclu.unibas.ch

	Abstract

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
Abstract Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted peptide, which is implicated in human atherosclerosis and fibrotic disorders such as systemic scleroderma. CTGF is a member of the peptide family that includes serum-induced immediate early gene products, a v-src–induced peptide, and a putative proto-oncogene. The CTGF gene family is a modular protein and is conserved throughout evolution. CTGF mRNA has been found in the human, mouse, chicken, frog, and fly. The functions of the CTGF gene family include embryogenesis, wound healing, and regulation of extracellular matrix production. Human CTGF is undetectable in normal blood vessels but overexpressed in atherosclerotic lesions, suggesting an important role in atherogenesis.

Key Words: atherosclerosis • development • fibrosis • gene expression • gene cloning

	Introduction

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
The cysteine-rich secreted protein Cyr61 was the first member of the CTGF gene family to be identified. This protein, originally known as 3CH61, was isolated by Lau and Nathans¹ in 1985 from mouse fibroblasts stimulated with serum and PDGF. Eleven years later, seven related proteins, including the chicken ortholog for Cyr61, CEF10² ; human, mouse, and Xenopus laevis CTGF^{3 4 5} ; and human, chicken, and Xenopus laevis nov^{5 6 7} have been isolated, cloned, sequenced, and characterized as belonging to the CTGF gene family. CTGF family members (with the exception of nov) are immediate early growth-responsive genes that are thought to regulate cell proliferation, differentiation, embryogenesis, and wound healing. Sequence homology between members of the CTGF gene family is quite striking; however, functions of these proteins in vitro range from growth stimulatory (ie, human CTGF) to growth inhibitory (ie, chicken nov and also possibly hCTGF).^{8 9} The physiological function and significance of the CTGF gene family in vivo remain largely unknown, which is reflected in the small number of studies (approximately 30) published over the past 10 years.

We have recently cloned human CTGF from human aorta by a differential cloning strategy and found that CTGF is expressed at very high levels in atherosclerotic but not in normal human blood vessels.¹⁰ Therefore, we have proposed that CTGF may play an important pathophysiological role in human atherosclerosis. This review represents a comprehensive overview of the emerging CTGF gene family and an attempt to illuminate the role of CTGF in human atherosclerosis.

	Structure of the CTGF Gene Family

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
The CTGF gene family is characterized by a high degree of amino acid sequence homology, ranging from 50% to 90% (Fig 1A). All members of the CTGF gene family possess a secretory signal peptide at the N terminus, indicating that they are secreted proteins. In fact, human and mouse CTGF have been found in the conditioned medium of cultured endothelial cells and fibroblasts, respectively,^{3 4} and both nov and Cyr61 are mainly associated with the cell surface and extracellular matrix.^{9 11} All members of the CTGF gene family contain 38 totally conserved cysteine residues, which are clustered in two segments (22 at the N-terminal region and 16 at the C terminal), separated by a region that varies in length and amino acid composition. Detailed analysis revealed four distinct protein modules in this CTGF protein family,¹² which are (1) an IGF binding domain, with the conserved putative IGF binding motif Gly-Cys-Gly-Cys-Cys-X-X-Cys (X is any amino acid) located within the amino-terminal portion of all IGF binding proteins^{13 14 15} ; (2) a von Willebrand factor type C repeat, which is thought to participate in oligomerization and protein complex formation¹⁶ ; (3) a thrombospondin type 1 repeat, which is thought to be involved in binding to both soluble and matrix macromolecules, and in particular to sulfated glycoconjugates¹⁷ ; and (4) a C-terminal module, which is homologous to slit, a protein involved in development of midline glia and commissural axon pathways in Drosophila,¹⁸ and may represent a dimerization domain or be involved in receptor binding (Fig 1B).

View larger version (79K): [in this window] [in a new window]   Figure 1.

These conserved protein modules are also reflected in the genomic organization of the CTGF gene family, which comprises five exons with fairly constant sizes and four introns with variable size (Fig 1C).⁵ Interestingly, the five exons correspond to the coding regions of the four protein modules, with the first exon encoding the signal peptide.¹⁹ Possibly, this structural domain conservation may represent the results of domain fusion during evolution, culminating in the convergence of several functional domains in a single polypeptide.²⁰

Despite the similarity in the protein coding region, both the promoter and the 3' untranslated region diverge considerably between CTGF family members, indicating differential regulation of the expression of individual proteins.^{19 21 22 23} Indeed, human nov (novH) and human CTGF (hCTGF) are differentially expressed in human glioma cell lines.²² novH mRNA levels vary in different glioma-derived cell lines and are normally present at low or undetectable levels. In contrast, hCTGF mRNA is normally expressed at high levels in these cell lines and is found to be inversely correlated with nov mRNA levels.²² Furthermore, a novel TGF-ß–responsive element is present in the promoter region of both human and mouse CTGF genes that is not present in the nov or Cyr61 gene.¹⁹

The diversity in the 3' untranslated region of the CTGF gene family may result in considerable differences of mRNA half-life. For example, the half-life of CTGF mRNA is only 10 to 15 minutes in NIH 3T3 cells,⁴ while that of nov transcripts in quiescent CEFs is about 8 hours.⁹ This difference may be due to the presence of several AUUUA motifs in the 3' untranslated region of the CTGF gene that are absent in nov and novH genes. This motif is known to confer mRNA instability.²⁴

	Functions of CTGF Gene Family Proteins

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
The presence of four conserved structural modules covering nearly the entire molecule suggests that CTGF protein family proteins may have multiple functions. Unfortunately, for many years, the investigation of the physiological functions of the CTGF gene family has been hampered by the lack of purified or recombinant protein. Due to the high content of cysteine in CTGF protein family members (11% of the total amino acid content), CTGF protein production is relatively difficult.^{10 20} Recently, two research groups have been successful in producing recombinant hCTGF and Cyr61 protein, using the baculovirus expression system.^{8 20}

	CTGF

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
Human CTGF, a 349–amino acid polypeptide, was first discovered by Bradham et al³ in 1991 by screening a HUVEC cDNA expression library by using a polyclonal anti-PDGF antibody. At about the same time, Ryseck et al⁴ and Brunner et al²⁵ independently isolated mouse CTGF (Fisp12/ßIG-M2) from serum-stimulated NIH 3T3 cells and TGF-ß–stimulated mouse AKR-2B cells, respectively, by using differential cloning techniques. The gene for human CTGF is localized to chromosome 6q23.1,⁷ and the mouse CTGF is at position [10A3-10B1] on the murine genome.⁴ The deduced molecular weight of both human and mouse CTGF is 38 kD. However, due to posttranslational modification (glycosylation), the human CTGF protein is calculated to be 42 kD when resolved on denaturing SDS-polyacrylamide gels, suggesting the utilization of two potential N-linked glycosylation sites at asparagine residues 28 and 225 (Oemar et al, unpublished results). In contrast, the deduced mouse CTGF protein sequence does not contain a consensus sequence for N-linked glycosylation, which was confirmed by pulse-chase experiments using tunicamycin, which blocks the addition of N-linked carbohydrate units to asparagine.⁴ The predicted protein sequence of human CTGF shares 90% amino acid identity to mouse CTGF (Fisp12/ßIG-M2), 53% amino acid identity to novH, 52% amino acid identity to nov or xnov, and 50% amino acid identity to CEF-10 or Cyr61.⁵ In adult tissue, human CTGF mRNA is expressed in heart, brain, placenta, lung, liver, muscle, kidney, and pancreas as a single transcript of 2.4 kb, being most abundant in the kidney (30-fold higher than brain).¹⁰ In contrast, Ryseck et al⁴ found that mouse CTGF is expressed at high levels in both the kidney and brain of adult mice (Table). More recently, Xin et al²² also found a less prominent 7.0-kb and 3.5-kb CTGF mRNA species in human glioma cell lines. However, it is not yet clear whether the 7.0-kb and 3.5-kb transcripts in these cells are the result of alternative splicing or originate from two distinct CTGF-related genes. Both human and mouse CTGF have been found in culture media of serum-stimulated HUVECs and fibroblasts, respectively. The CTGF protein is efficiently secreted into the culture medium after stimulation of quiescent NIH 3T3 cells, and the half-life is calculated to be 60 to 90 minutes, as determined by pulse-chase experiments.⁴

View this table: [in this window] [in a new window]   Table 1. mRNA Expression of CTGF Gene Family in Adult Tissue During Embryonic Development and Cultured Cells1

Thus far, the physiological function of CTGF both in vitro and in vivo is not clear. However, Bradham et al³ found that HUVEC-conditioned medium containing human CTGF is mitogenic to NRK cells in vitro and that protein extracts of Xenopus oocytes injected with hCTGF mRNA are chemotactic to NIH 3T3 cells. Subsequently, the same research group found that in human skin fibroblasts, CTGF mRNA is induced specifically by TGF-ß but not by PDGF, epidermal growth factor, or basic fibroblast growth factor.²⁶ In addition, TGF-ß and CTGF mRNA are coordinately overexpressed during wound repair in an in vivo model for wound healing in the rat, indicating that CTGF may be one of the downstream effectors of TGF-ß.²⁶ Indeed, Grotendorst et al¹⁹ have recently found a novel TGF-ß–responsive element with the consensus sequence 5'-GTGTCAAGGGGTC-3' located between positions -162 and -128 of the CTGF promoter sequence. TGF-ß induced a 25-fold to 30-fold increase in luciferase activity in NIH-3T3 fibroblasts that had been transfected with a promoter construct containing the 5' flanking region of the human CTGF gene linked to the luciferase reporter gene. Point mutations in this TGF-ß–responsive element resulted in a complete loss of TGF-ß induction.¹⁹

Since TGF-ß has been shown to participate in numerous pathological processes, including atherosclerosis,²⁷ CTGF might represent a downstream target for TGF-ß activation and play a role in the development and progression of atherosclerosis. In fact, we have recently isolated CTGF from a human aorta cDNA library using a differential cloning strategy.¹⁰ The rationale behind this cloning strategy was based on the knowledge that atherosclerotic lesions normally do not develop uniformly in all blood vessels; ie, atherosclerotic lesions are typically located in the aorta and its major branches, such as the carotid and coronary arteries. In contrast, the internal mammary artery, which is also a major branch frequently used as a coronary bypass vessel, is normally free of atherosclerotic lesions even in patients with severe coronary heart disease and in old age.²⁸ We differentially screened 20 000 human aorta cDNA clones against an internal mammary artery cDNA library, and a full-length CTGF cDNA (2312 bp, Genbank accession No. x78947) was found to be among 60 other differentially expressed genes. Northern blot analysis confirmed that hCTGF is indeed differentially expressed at 50-fold to 100-fold higher levels in atherosclerotic blood vessels than in normal arteries (Fig 2A). Moreover, CTGF mRNA expression in VSMCs is also regulated by TGF-ß. CTGF mRNA increased 20-fold over basal level after stimulation with TGF-ß and only 3-fold to 6-fold after PDGF stimulation (Fig 2B), indicating that in human blood vessels, as in fibroblasts, CTGF is indeed a downstream target for TGF-ß activation and may therefore participate in the pathogenesis of atherosclerosis.

View larger version (26K): [in this window] [in a new window]   Figure 2. A, Northern blot analysis of hCTGF expression in human aorta. Poly(A)+ RNA isolated from four white males (5 µg each) was analyzed. hCTGF expression in patients, aged 31 years (lane 1), 43 years (lane 2), 66 years (lane 3), and 71 years (lane 4) are shown. hCTGF mRNA in the aorta of the 66-year-old patient was 100-fold higher than in the 31-year-old patient. B, Regulation of CL59/hCTGF mRNA expression in human aortic VSMCs. Northern blot analysis of quiescent (Q) VSMCs stimulated with TGF-ß or PDGF-AA/BB (20 µg total RNA per lane) is shown. Rehybridization with human myosin heavy chain cDNA probe served as control.

Early atherosclerotic lesions are characterized by accumulation of inflammatory cells and intimal smooth muscle cell proliferation, migration, and extracellular matrix deposition.^{27 29} Serum or blood cell–derived factors such as TGF-ß participate in these processes.^{27 29 30 31 32} In particular, TGF-ß1 induces overproduction of extracellular matrix proteins in intimal VSMCs.³¹ Furthermore, direct in vivo transfer of an expression vector carrying the TGF-ß1 gene into arteries stimulated extracellular matrix production and intimal and medial hyperplasia.³³ During the development of atherosclerosis, CTGF could mediate some of the effects of TGF-ß, ie, stimulation of extracellular matrix production. Indirect evidence supporting this hypothesis is provided by the fact that high-level expression of CTGF mRNA and protein occurs in VSMCs and endothelial cells of advanced human atherosclerotic lesions but not in normal arteries.¹⁰ In addition, VSMCs expressing CTGF were localized predominantly in areas with extracellular matrix accumulation and especially along the shoulder of fibrous caps, suggesting that CTGF may regulate the extracellular matrix production in these cells and thus induce intimal thickening. On the other hand, CTGF may also help to stabilize the fibrous cap by increasing the extracellular matrix production in this area (Fig 3). In fact, recombinant CTGF protein produced in baculovirus has been found to stimulate type I collagen and fibronectin production in NRK fibroblasts.⁸ When injected subcutaneously, recombinant CTGF also induces granulation tissue formation and fibrosis in neonatal NIH Swiss mice.⁸ In addition, recombinant CTGF stimulates DNA synthesis in cultured fibroblasts.

View larger version (133K): [in this window] [in a new window]   Figure 3. Trichrome staining (Goldner-Weigert's elastica) (A) and in situ hybridization (B) of a serial section of an atherosclerotic carotid artery. hCTGF-expressing cells are localized along the shoulder of fibrous caps (arrowheads). hCTGF mRNA-expressing cells are indicated by the accumulation of silver grains. Connective tissue is indicated by green, elastic fiber is dark purple, cytosol is red, and nuclei are dark brown. Original magnification x100 for A and x200 for B.

These findings immediately raise the question of whether or not CTGF also stimulates cell proliferation in VSMCs. In human carotid arteries, CTGF-expressing cells are nonproliferating cells, as shown by immunostaining with anti–proliferating cell nuclear antigen,¹⁰ suggesting that in vivo CTGF does not stimulate vascular cell proliferation. However, we do not know whether CTGF stimulates the proliferation of cultured VSMCs in vitro. Also, we do not know what other growth factors besides TGF-ß regulate CTGF expression in vivo or in vitro. Do lipids and lipoproteins also play a role? It is also not clear how CTGF signals to VSMCs to regulate cell function. Does CTGF bind to its own receptor, or could it also bind to the PDGF receptor? High-level expression of CTGF in endothelial cells at the luminal site of advanced atherosclerotic lesions as well as in the newly formed vasa vasorum inside the plaques suggests important functions of CTGF in these cells, eg, by inducing angiogenesis.

Depending on the site of expression, CTGF could be either friend or foe. For example, CTGF may be necessary for normal wound repair in the skin.²⁶ In patients with systemic sclerosis, however, overexpression of CTGF in skin fibroblasts may be disastrous.³⁴ Similarly, overexpression of CTGF in other organs, such as kidney, lung, or liver, may trigger pathological processes such as glomerulosclerosis, lung fibrosis, or liver cirrhosis. In atherosclerosis, high-level expression of CTGF may be responsible for extracellular matrix accumulation and thus progression of atherosclerotic lesions.¹⁰ However, increased CTGF expression along the fibrous cap may be advantageous; ie, increased extracellular matrix production in this area may stabilize the fibrous cap and reduce the risk of plaque rupture.

	nov, novH, and xnov

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
In 1992, Joliot et al⁶ cloned and characterized the nov gene from myeloblastosis-associated virus type 1–induced nephroblastoma in the chicken. nov mRNA was found to be expressed at high levels in all nephroblastomas tested but was undetectable in adult chicken kidney. An amino-terminal truncated form of nov was found to induce transformation of CEFs.⁶ Therefore, nov was first thought to represent a cellular proto-oncogene. Consistent with this hypothesis, the full-length nov was found to be growth inhibitory when overexpressed in CEFs.⁶ Recently, Scholz et al⁹ have shown that nov mRNA is downregulated in p60^v-src-transformed CEFs. nov transcripts were also found to be downregulated in mitogen-stimulated CEFs,⁹ and novH expression in Wilms' tumors is less than in normal kidney,³⁵ again suggesting that nov may have a growth-suppressor activity. In fact, nov may represent the first member of the CTGF family to exhibit a negative effect on cell growth and may balance the mitogenic effects of the other members. Indeed, in glioma cell lines, novH and hCTGF mRNA are normally coexpressed, and in some cell lines novH and hCTGF expression were inversely correlated.²²

In adult tissue, chicken nov is expressed in the brain, lung, and spleen but not in the kidney. Human nov, however, is also expressed in the kidney.³⁶ Ying and King⁵ recently cloned and characterized xnov, the Xenepus laevis ortholog of the chicken nov. xnov mRNA is expressed at relatively constant levels throughout oogenesis and embryogenesis (Table) and thus does not appear to be developmentally regulated.

So far, no one has looked at nov expression in blood vessels. It is also not yet known whether novH is expressed in atherosclerotic lesions and if so, in which cell type. Future studies should evaluate whether or not novH participates in atherogenesis.

	Cyr61 and CEF10

Top Abstract Introduction Structure of the CTGF... Functions of CTGF Gene... CTGF nov, novH, and xnov Cyr61 and CEF10 References

 
Both mouse Cyr61 and the avian ortholog CEF10 were isolated by differential cloning techniques from fibroblasts.^{1 2} In adult tissue, CEF10 mRNA expression is restricted to the lung. So far, the function of CEF10 is unknown. However, recombinant Cyr61 protein produced in the baculovirus expression system promotes cell proliferation, migration, and adhesion in NIH 3T3 cells and HUVECs. Interestingly, Cyr61 protein does not have detectable mitogenic activity by itself but potentiates mitogenic effects of other growth factors, such as basic fibroblast growth factor on fibroblasts and endothelial cells.²⁰ Due to the high degree of sequence similarity between Cyr61 and CEF10 (78% amino acid sequence identity), it is likely that CEF10 may also share some of the functions of Cyr61.

In adult tissue, Cyr61 was expressed in all major organs tested (see Table).³⁷ During embryonic development in mice, Cyr61 mRNA expression correlates with chondrogenesis and is particularly high in the aorta and bulbus arteriosus of the embryo, suggesting a role for Cyr61 in regulating the embryonic development of skeletal and circulatory systems.^{37 38} Interestingly, Cyr61 also shares sequence similarities with two Drosophila genes, twisted gastrulation³⁹ and short gastrulation.⁴⁰ Both of these genes interact with decapentaplegic (a morphogenic protein belonging to the TGF-ß gene family) to control dorsal-ventral patterning of the Drosophila embryo. Taken together, these data show that Cyr61 appears to play an important role during embryonic development.

The human counterpart for Cyr61/CEF10 has not yet been found. In fact, we do not know whether the CTGF protein family also plays a role during human embryonic development, but given the high degree of sequence conservation among the CTGF family members, we expect that this will be the case. As with novH, we do not yet know anything about the role of Cyr61/CEF10 in the pathophysiology of blood vessels. However, since Cyr61 is highly expressed and regulated during the development of the circulatory system in mouse embryo, it is likely that it will also play a role in disease development in adults.

Thus, in summary, atherosclerosis has become more complex as we discover ever-increasing numbers of molecules involved. Human CTGF may represent only one piece of the puzzle in this complex picture, but possibly an important one. For example, hCTGF is undetectable in normal blood vessels but dramatically overexpressed in atherosclerotic lesions. hCTGF may represent the downstream effectors for TGF-ß and a key regulator of extracellular matrix production in the vessel wall. However, we are still at the very beginning of understanding the physiological function of the CTGF gene family, and the exact mechanism by which CTGF regulates endothelial or VSMC function remains unknown. Identification of the CTGF receptor and quantitation of binding sites, as well as understanding how CTGF signaling results in extracellular matrix production, will remain important goals of future research.

	Selected Abbreviations and Acronyms

 

CEF = chicken embryonic fibroblast CTGF = connective tissue growth factor IGF = insulin-like growth factor NIH = National Institutes of Health PDGF = platelet-derived growth factor TGF = transforming growth factor VSMC = vascular smooth muscle cell

View larger version (17K): [in this window] [in a new window]   Figure .

View larger version (23K): [in this window] [in a new window]   Figure 01C. (Above and facing page) A, Alignment of deduced amino acid sequences of the CTGF gene family. Gray shaded areas indicate amino acid identities in all six sequences. All 38 conserved cysteine residues are shown (). The putative IGF-BP sequence GCGCCXXC is underlined. The deduced amino acid sequence of hCTGF is 90% identical to mCTGF, 52% identical to nov or xnov, and 50% identical to Cyr61 and CEF10. B, Domain structure of the CTGF gene family. CTGF protein family members contain four distinct protein modules, which are (1) an IGF binding domain, (2) a von Willebrand factor type C repeat, (3) a thrombospondin type 1 repeat, and (4) a C-terminal module. C, Genomic organization of the CTGF gene family. CTGF gene family proteins comprise five exons with fairly constant sizes and four introns of variable size. The five exons correspond to the coding regions of the four protein modules, with the first exon encoding the signal peptide.

	Acknowledgments

 
This work was supported by Swiss National Science Foundation grants (32-32541.91 and 3100-047119.96/1), the Schweizerische Mobiliarversicherung, and the Swiss Cardiology Foundation.

Received April 7, 1997; accepted April 18, 1997.

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