Skip to main content
SpringerLink
Log in

An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin

  • Review
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

The principal aim of this historical review is to present the processes by which the different aspects of CCN2/CTGF/Hcs24 were discovered by different groups and how much CCN2/CTGF, by being integrated into CCN family, has contributed to the establishment of the basic concepts regarding the role and functions of this new class of proteins. This review should be particularly useful to new investigators who have recently entered this exciting field of study and also provides a good opportunity to acknowledge the input of those individuals who participated in the development of this scientific field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CCN:

Cysteine-rich 61, Connective tissue growth factor, Nephroblastoma-overexpressed

CCN2:

CCN family member 2, Connective tissue growth factor

Hcs24:

Hypertrophic chondrocyte-specific gene product 24

CCN3:

CCN family member 3, Nephroblastoma-overexpressed

ECM:

Extracellular matrix

MMP:

Matrix metalloproteinase

TGF-β:

Transforming growth factor-beta

BMP:

Bone morphogenetic protein

VEGF:

Vascular endothelial growth factor

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

EGF:

Epidermal growth factor

PDGF:

Platelet-derived growth factor

RANK:

Receptor activator of nuclear factor kappa-B

RANKL:

Receptor activator of nuclear factor kappa-B ligand

OPG:

Osteoprotegerin

IGFBP:

Insulin-like growth factor-binding protein

VWC:

Willebrand factor type C repeat

TSP:

Thrombospondin

HUVEC:

Human umbilical vein endothelial cells

HCS-2/8:

Human chondrosarcoma derived chondrocytic cell line 2/8

CAESAR:

cis-acting element of structure-anchored repression

References

  • Abreu JG, Ketpura NI, Reversade B, De Robertis EM (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol 4(8):599–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Almendral JM, Sommer D, Macdonald-Bravo H, Burckhardt J, Perera J, Bravo R (1988) Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol 8(5):2140–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson HC, Hodges PT, Aguilera XM, Missana L, Moylan PE (2000) Bone morphogenetic protein (BMP) localization in developing human and rat growth plate, metaphysis, epiphysis, and articular cartilage. J Histochem Cytochem 48(11):1493–1502

    Article  CAS  PubMed  Google Scholar 

  • Aoyama E, Hattori T, Hoshijima M, Araki D, Nishida T, Kubota S, Takigawa M (2009) N-terminal domains of CCN protein 2/connective tissue growth factor bind to aggrecan. Biochem J 420:413–420

    Article  CAS  PubMed  Google Scholar 

  • Aoyama E, Kubota S, Takigawa M (2012) CCN2/CTGF binds to fibroblast growth factor receptor 2 and modulates its signaling. FEBS Lett 586(24):4270–4275

    Article  CAS  PubMed  Google Scholar 

  • Aoyama E, Kubota S, Khattab HM, Nishida T, Takigawa M (2015) CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG. Bone 73:242–248

    Article  CAS  PubMed  Google Scholar 

  • Babic AM, Chen CC, Lau LF (1999) Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19:2958–2966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ball DK, Surveyor GA, Diehl JR, Steffen CL, Uzumcu M, Mirando MA, Brigstock DR (1998) Characterization of 16- to 20-kilodalton (kDa) connective tissue growth factors (CTGFs) and demonstration of proteolytic activity for 38-kDa CTGF in pig uterine luminal flushings. Biol Reprod 59(4):828–835

    Article  CAS  PubMed  Google Scholar 

  • Banerjee SK, Maity G, Haque I, Ghosh A, Sarkar S, Gupta V, Campbell DR, Von Hoff D, Banerjee S (2016) Human pancreatic cancer progression: an anarchy among CCN-siblings. J Cell Commun Signal 10(3):207–216

    Article  PubMed  PubMed Central  Google Scholar 

  • Bork P (1993) The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327:125–130

    Article  CAS  PubMed  Google Scholar 

  • Bradham DM, Igarashi A, Potter RL, Grotendorst GR (1991) Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 114:1285–1294

    Article  CAS  PubMed  Google Scholar 

  • Brigstock DR (1999) The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20:189–206

    CAS  PubMed  Google Scholar 

  • Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA (1997) Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin- regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem 272:20275–20282

    Article  CAS  PubMed  Google Scholar 

  • Brigstock DR, Goldshemeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H (2003) Proposal for a unified CCN nomenclature. Mol Pathol 56:127–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunner A, Chinn J, Neubauer M, Purchio AF (1991) Identification of a gene family regulated by transforming growth factor b. DNA Cell Biol 10:293–300

    Article  CAS  PubMed  Google Scholar 

  • Charrier A, Brigstock DR (2013) Regulation of pancreatic function by connective tissue growth factor (CTGF, CCN2). Cytokine Growth Factor Rev 24(1):59–68

    Article  CAS  PubMed  Google Scholar 

  • Chen CC, Chen N, Lau LF (2001) The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem 276:10443–10452

    Article  CAS  PubMed  Google Scholar 

  • Chujo S, Shirasaki F, Kawara S, Inagaki Y, Kinbara T, Inaoki M, Takigawa M, Takehara K (2005) Connective tissue growth factor causes persistent proa2(I) collagen gene expression induced by transforming growth factor-b in a mouse fibrosis model. J Cell Physiol 203(2):447–456

    Article  CAS  PubMed  Google Scholar 

  • Cicha I, Garlichs CD, Daniel WG, Goppelt-Struebe M (2004) Activated human platelets release connective tissue growth factor. Thromb Haemost 91(4):755–760

    CAS  PubMed  Google Scholar 

  • Crawford LJ, Irvine AE (2016) The role of the CCN family of proteins in blood cancers. J Cell Commun Signal 10(3):197–205

    Article  PubMed  PubMed Central  Google Scholar 

  • Dammeier J, Beer HD, Brauchle M, Werner S (1998) Dexamethasone is a novel potent inducer of connective tissue growth factor expression. Implications for glucocorticoid therapy. J Biol Chem 273(29):18185–18190

    Article  CAS  PubMed  Google Scholar 

  • Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR (1999) Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J 13(13):1774–1786

    Article  CAS  PubMed  Google Scholar 

  • Eguchi T, Kubota S, Kondo S, Shimo T, Hattori T, Nakanishi T, Kuboki T, Yatani H, Takigawa M (2001) Regulatory mechanism of human connective tissue growth factor (CTGF/Hcs24) gene expression in a human chondrocytic cell line, HCS-2/8. J Biochem (Tokyo) 130:79–87

    Article  CAS  Google Scholar 

  • Eguchi T, Kubota S, Kondo S, Kuboki T, Yatani H, Takigawa M (2002) A novel cis-element that enhances connective tissue growth factor gene expression in chondrocytic cells. Biochem Biophys Res Commun 295:445–451

    Article  CAS  PubMed  Google Scholar 

  • Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR (1996) Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 107(3):404–411

    Article  CAS  PubMed  Google Scholar 

  • Gao R, Brigstock DR (2004) Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Hepatol 40:431–438

    Article  CAS  PubMed  Google Scholar 

  • Grotendorst GR, Okochi H, Hayashi N (1996) A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ 7:469–480

    CAS  PubMed  Google Scholar 

  • Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277(39):36288–36295

    Article  CAS  PubMed  Google Scholar 

  • Hoshijima M, Hattori T, Aoyama E, Nishida T, Yamashiro T, Takigawa M (2012) Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes. FEBS J 279(19):3584–3597

    Article  CAS  PubMed  Google Scholar 

  • Huang G, Brigstock DR (2012) Regulation of hepatic stellate cells by connective tissue growth factor. Front Biosci (Landmark Ed) 17:2495–2507

    Article  CAS  Google Scholar 

  • Igarashi A, Okochi H, Bradham DM, Grotendorst GR (1993) Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell 4:637–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Fujimoto M, Grotendorst GR, Takehara K (1996) Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol 106:729–733

    Article  CAS  PubMed  Google Scholar 

  • Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, Makino K, Ikeda E, Takata S, Kobayashi K, Okada Y (2002) Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J 16(2):219–221

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Okada H, Kobayashi T, Watanabe Y, Kanno Y, Kopp JB, Nishida T, Takigawa M, Ueno M, Nakamura T, Suzuki H (2003) Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. FASEB J 17(2):268–270

    Article  CAS  PubMed  Google Scholar 

  • Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779–2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jedsadayanmata A, Chen CC, Kireeva ML, Lau LF, Lam SC (1999) Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/mouse connective tissue growth factor is mediated through integrin alpha(IIb)beta(3). J Biol Chem 274:24321–24327

    Article  CAS  PubMed  Google Scholar 

  • Joyce ME, Jingushi S, Bolander ME (1990) Transforming growth factor-beta in the regulation of fracture repair. Orthop Clin North Am 21(1):199–209

    CAS  PubMed  Google Scholar 

  • Kadota H, Nakanishi T, Asaumi K, Yamaai T, Nakata E, Mitani S, Aoki K, Aiga A, Inoue H, Takigawa M (2004) Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24/CCN2) during distraction osteogenesis. J Bone Miner Metab 22(4):293–302

    Article  CAS  PubMed  Google Scholar 

  • Kanyama M, Kuboki T, Akiyama K, Nawachi K, Miyauchi FM, Yatani H, Kubota S, Nakanishi T, Takigawa M (2003) Connective tissue growth factor expressed in rat alveolar bone regeneration sites after tooth extraction. Archs. Oral Biol 48:723–730

    Article  CAS  Google Scholar 

  • Kawata K, Eguchi T, Kubota S, Kawaki H, Oka M, Minagi S, Takigawa M (2006) Possible role of LRP1, a CCN2 receptor, in chondrocytes. Biochem Biophys res Commun 345(2):552–559

    Article  CAS  PubMed  Google Scholar 

  • Khattab HM, Aoyama E, Kubota S, Takigawa M (2015) Physical interaction of CCN2 with diverse growth factors involved in chondrocyte differentiation during endochondral ossifyication. J Cell Commun Signal 9(3):247–254

    Article  PubMed  PubMed Central  Google Scholar 

  • Kikuchi K, Kadono T, Ihn H, Sato S, Igarashi A, Nakagawa H, Tamaki K, Takehara K (1995) Growth regulation in scleroderma fibroblasts: increased response to transforming growth factor-beta 1. J Invest Dermatol 105:128–132

    Article  CAS  PubMed  Google Scholar 

  • Kikuchi T, Kubota S, Asaumi K, Kawaki H, Nishida T, Kawata K, Mitani S, Tabata Y, Ozaki T, Takigawa M (2008) Promotion of bone regeneration by CCN2 incorporated into gelatin hydrogel. Tissue Eng A 14:1089–1098

    Article  CAS  Google Scholar 

  • Kimura Y, Nakanishi T, Murakami T, Tamura T, Hattori T, Takahashi K, Takigawa M (1995) Isolation of a gene predominantly expressed in chondrocytes from a human chondrocyte-derived chondrocytic cell line. Seikagaku 67:876 (in Japanese)

    Google Scholar 

  • Kireeva ML, Latinkić BV, Kolesnikova TV, Chen CC, Yang GP, Abler AS, Lau LF (1997) Cyr61 and Fisp12 are both ECM-associated signaling molecules: activities, metabolism, and localization during development. Exp Cell Res 233(1):63–77

    Article  CAS  PubMed  Google Scholar 

  • Klaassen I, van Geest RJ, Kuiper EJ, van Noorden CJ, Schlingemann RO (2015) The role of CTGF in diabetic retinopathy. Exp Eye Res 133:37–48

    Article  CAS  PubMed  Google Scholar 

  • Kleer CG (2016) Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal 10(3):217–222

    Article  PubMed  PubMed Central  Google Scholar 

  • Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Kanto T, Hiramatsu N, Kubota S, Takigawa M, Tomimaru Y, Tomokuni A, Nagano H, Doki Y, Mori M, Hayashi N (2011) Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. J Clin Invest 121:3343–3356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondo Y, Nakanishi T, Takigawa M, Ogawa N (1999) Immunohistochemical localization of connective tissue growth factor in the rat central nervous system. Brain Res 834(1–2):146–151

    Article  CAS  PubMed  Google Scholar 

  • Kondo S, Kubota S, Eguchi T, Hattori T, Nakanishi T, Sugawara T, Takigawa M (2000) Characterization of a mouse ctgf 3'-UTR segment that mediates repressive regulation of gene expression. Biochem Biophys Res Commun 278(1):119–124

  • Kondo S, Kubota S, Shimo T, Nishida T, Yoshimichi G, Eguchi T, Sugahara T, Takigawa M (2002) Connective tissue growth factor induced by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23:769–776

    Article  CAS  PubMed  Google Scholar 

  • Kothapalli D, Hayashi N, Grotendorst GR (1998) Inhibition of TGF-beta-stimulated CTGF gene expression and anchorage-independent growth by cAMP identifies a CTGF-dependent restriction point in the cell cycle. FASEB J 12(12):1151–1161

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Mukudai Y, Moritani NH, Nakao K, Kawata K, Takigawa M (2005) Transcriptional repression by the cis-acting element of structure-anchored repression (CAESAR) of human ctgf/ccn2 mRNA. FEBS Lett 579:3751–3758

  • Kubota S, Takigawa M (2007a) CCN family proteins and angiogenesis: from embryo to adulthood. Angiogiogenesis 10(1):1–11

    Article  CAS  Google Scholar 

  • Kubota S, Takigawa M (2007b) Role of CCN2/CTGF/Hcs24 in bone growth. Int Rev Cytol 257:1–41

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Takigawa M (2011) The role of CCN2 in cartilage and bone development. J Cell Commun Signal 5:209–2017

    Article  PubMed  PubMed Central  Google Scholar 

  • Kubota S, Takigawa M (2013) The CCN family acting throughout the body: recent research developments. Biomol Concept 5:477–494

    Google Scholar 

  • Kubota S, Takigawa M (2015) Cellular and molecular actions of CCN2/CTGF and their role under physiological and pathological conditions. Clin Sci 128(3):181–196

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Hattori T, Nakanishi T, Takigawa M (1999) Involvement of cis-acting repressive element(s) in the 3′-untranslated region of human connective tissue growth factor gene. FEBS Lett 450:84–88

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Kondo S, Eguchi T, Hattori T, Nakanishi T, Pomerantz RJ, Takigawa M (2000) Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: similarities to retroviral RNA-protein interactions. Oncogene 19:4773–4786

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Moritani NH, Kawaki H, Mimura H, Minato M, Takigawa M (2003) Transcriptional induction of connective tissue growth factor/ hypertrophic chondrocyte specific 24 (CTGF/Hcs24) gene by dexamethasone in human chondrocytic cells. Bone 33:694–702

    Article  CAS  PubMed  Google Scholar 

  • Kubota S, Kawata K, Yanagita T, Doi H, Kitoh T, Takigawa M (2004) Abundant retention and release of connective tissue growth factor (CTGF/CCN2) by platelets. J Biochem 136:279–282

    Article  CAS  PubMed  Google Scholar 

  • Lau LF (2016) Cell surface receptors for CCN proteins. J Cell Commun Signal 10(2):121–127

    Article  PubMed  PubMed Central  Google Scholar 

  • Lau LF, Lam SC (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248:44–57

    Article  CAS  PubMed  Google Scholar 

  • Leask A (2013) CCN2: a novel, specific and valid target for anti-fibrotic drug intervention. Expert Opin Ther Targets 17(9):1067–1071

    Article  CAS  PubMed  Google Scholar 

  • Leask A (2015) Getting to the heart of the matter: new insights into cardiac fibrosis. Circ Res 116(7):1269–1276

    Article  CAS  PubMed  Google Scholar 

  • Leask A (2017) CCN2 in Skin Fibrosis. Methods Mol Biol 1489:417–421

    Article  CAS  PubMed  Google Scholar 

  • Leask A, Holmes A, Abraham DJ (2002) Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep 4:136–142

    Article  PubMed  Google Scholar 

  • Maeda A, Nishida T, Aoyama E, Kubota S, Lyons KM, Kuboki T, Takigawa M (2009) CCN family 2/connective tissue growth factor modulates BMP signaling as a signal conductor, which action regulayes the proliferation and differentiation of chondrocytes. J Biochem 145(2):207–216

    Article  CAS  PubMed  Google Scholar 

  • Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K (1999) Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol 181:153–159

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi T, Kimura Y, Tamura T, Ichikawa H, Yamaai Y, Sugimoto T, Takigawa M (1997) Cloning of a mRNA preferentially expressed in chondrocytes by differential display-PCR from a human chondrocytic cell line that is identical with connective tissue growth factor (CTGF) mRNA. Biochem Biophys Res Commun 234:206–210

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi T, Nishida T, Shimo T, Kobayashi K, Kubo T, Tamatani T, Tezuka K, Takigawa M (2000) Effects of CTGF/Hcs24, a product of a hypertrophic chondrocyte-specific gene, on the proliferation and differentiation of chondrocytes in culture. Endocrinology 141:264–273

    Article  CAS  PubMed  Google Scholar 

  • Nakata E, NakanishiT KA, Asaumi K, Yamaai T, Asano M, Nishida T, Mitani S, Inoue H, Takigawa M (2002) Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) during fracture healing. Bone 31(4):441–447

    Article  CAS  PubMed  Google Scholar 

  • Nawachi K, Inoue M, Kubota S, Nishida T, Yosimichi G, Nakanishi T, Kanyama M, Kuboki T, Yatani H, Yamaai T, Takigawa M (2002) Tyrosine kinase-type receptor ErbB4 in chondrocytes: interaction with connective tissue growth factor and distribution in cartilage. FEBS Lett 528(1–3):109–113

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Nakanishi T, Shimo T, Asano M, Hattori T, Tamatani T, Tezuka K, Takigawa M (1998) Demonstration of receptors specific for connective tissue growth factor on a human chondrocytic cell line (HCS-2/8). Biochem Biophys Res Commun 247:905–909

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Nakanishi T, Asano M, Shimo T, Takigawa M (2000) Effects of CTGF/Hcs24, a hypertrophic chondrocyte-specific gene product, on the proliferation and differentiation of osteoblastic cells in vitro. J Cell Physiol 184:197–206

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Kubota S, Nakanishi T, Kuboki T, Yosimichi G, Kondo S, Takigawa M (2002) CTGF/Hcs24, a hypertrophic chondrocyte specific gene product, stimulates the proliferation and expression of the cartilage phenotype but not hypertrophy or calcification or articular cartilage in culture. J Cell Physiol 192:55–63

  • Nishida T, Kubota S, Fukunaga T, Kondo S, Yosimichi G, Nakanishi T, Takano-Yamamoto T, Takigawa M (2003) CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes. J Cell Physiol 196:265–275

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Kubota S, Kojima S, Kuboki T, Nakao K, Kushibiki T, Tabata Y, Takigawa M (2004) Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor). J Bone Miner Res 19:1308–1319

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Emura K, Kubota S, Lyons KM, Takigawa M (2011) CCN family 2/ connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP). J Bone Miner Res 26:351–363

    Article  CAS  PubMed  Google Scholar 

  • Oemar BS, Luscher TF (1997) Connective tissue growth factor. Friend or foe? Arterioscler Thromb Vasc Biol 17:1483–1489

    Article  CAS  PubMed  Google Scholar 

  • Oemar BS, Werner A, Garnier JM, Do DD, Godoy N, Nauck M, Marz W, Rupp J, Pech M, Luscher TF (1997) Human connective tissue growth factor is expressed in advanced atherosclerotic lesions. Circulation 95:831–839

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi H, Oka T, Kusachi S, Nakanishi T, Takeda K, Nakahama M, Doi M, Murakami T, Ninomiya Y, Takigawa M, Tsuji T (1998) Increased expression of connective tissue growth factor in the infarct zone of experimentally induced myocardial infarction in rats. J Mol Cell Cardiol 30:2411–2422

    Article  CAS  PubMed  Google Scholar 

  • Perbal B (2001) NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 54:57–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perbal B (2004) CCN proteins:multifunctional signaling regulators. Lancet 363(9402):62–64

    Article  CAS  PubMed  Google Scholar 

  • Perbal A, Perbal B (2016) The CCN family of proteins:2 25th anniversary picture. J Cell Commun Signal 10:177–190

    Article  PubMed  PubMed Central  Google Scholar 

  • Perbal B, Takigawa M (eds) (2005) CCN proteins: a new family of cell growth and differentiation regulators. Imperial College Press, London, pp 19–59

    Book  Google Scholar 

  • Ricupero DA, Rishikof DC, Kuang PP, Poliks CF, Goldstein RH (1999) Regulation of connective tissue growth factor expression by prostaglandin E(2). Am J Phys 277(6 Pt 1):L1165–L1171

    CAS  Google Scholar 

  • Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, Narins RG (2000) Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. J Am Soc Nephrol 11(1):25–38

    CAS  PubMed  Google Scholar 

  • Riser BL, Barnes JL, Varani J (2015) Balanced regulation of the CCN family of matricellular proteins: a novel approach to the prevention and treatment of fibrosis and cancer. J Cell Commun Signal 9(4):327–339

    Article  PubMed  PubMed Central  Google Scholar 

  • Rysec R-P, Macdonald-Bravo H, Mattei M-G, Bravo R (1991) Structure, mapping, and expression of fisp-12, a growth factor-inducible gene encoding a secreted cyteine-rich protein. Cell Growth Differ 2:225–233

    Google Scholar 

  • Safadi FF, Xu J, Smock SL, Kanaan RA, Selim AH, Odgren PR, Marks SC Jr, Owen TA, Popoff SN (2003) Expression of connective tissue growth factor in bone: its role in osteoblast proliferation and differentiation in vitro and bone formation in vivo. J Cell Physiol 196(1):51–62

    Article  CAS  PubMed  Google Scholar 

  • Sato S, Nagaoka T, Hasegawa M, Tamatani T, Nakanishi T, Takigawa M, Takehara K (2000) Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 27:149–154

    CAS  PubMed  Google Scholar 

  • Schild C, Trueb B (2004) Three members of the connective tissue growth factor family CCN are differentially regulated by mechanical stress. Biochim Biophys Acta 1691(1):33–40

    Article  CAS  PubMed  Google Scholar 

  • Schober JM, Chen N, Grzeszkiewicz TM, Jovanovic I, Emeson EE, Ugarova TP, Ye RD, Lau LF, Lam SC (2002) Identification of integrin alpha(M)beta(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions. Blood 99(12):4457–4465

    Article  CAS  PubMed  Google Scholar 

  • Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR 3rd, Carmichael DF (2001) The low density lipoprotein receptor-related protein/alpha2- macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem 276:40659–40667

    Article  CAS  PubMed  Google Scholar 

  • Shimo T, Nakanishi T, Kimura Y, Nishida T, Ishizeki K, Matsumura T, Takigawa M (1998) Inhibition of endogenous expression of connective tissue growth factor by its antisense oligonucleotide and antisense RNA suppresses proliferation and migration of vascular endothelial cells. J Biochem (Tokyo) 124:130–140

    Article  CAS  Google Scholar 

  • Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem (Tokyo) 126:137–145

    Article  CAS  Google Scholar 

  • Shimo T, Kubota S, Kondo S, Nakanishi T, Sasaki A, Mese H, Matsumura T, Takigawa M (2001a) Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line. Cancer Lett 174:57–64

    Article  CAS  PubMed  Google Scholar 

  • Shimo T, Nakanishi T, Nishida T, Asano M, Sasaki A, Kanyama M, Kuboki T, Matsumura T, Takigawa M (2001b) Involvement of CTGF, a hypertrophic chondrocyte-specific gene product, in tumor angiogenesis. Oncology 61:315–322

    Article  CAS  PubMed  Google Scholar 

  • Shimo T, Wu C, Billings PC, Piddington R, Rosenbloom J, Pacifici M, Koyama E (2002) Expression, gene regulation, and roles of Fisp12/CTGF in developing tooth germs. Dev Dyn 224(3):267–278

  • Surveyor GA, Brigstock DR (1999) Immunohistochemical localization of connective tissue growth factor (CTGF) in the mouse embryo between days 7.5 and 14.5 of gestation. Growth Factors 17:115–124

    Article  CAS  PubMed  Google Scholar 

  • Takigawa M (2000) Physiological roles of connective tissue growth factor (CTGF/Hcs24): promotion of endochondral ossification, angiogenesis and tissue remodeling. In: Ikada Y, Shimizu Y (eds) Tissue engineering for therapeutic use, vol 4. Elsevier, Amsterdam, pp 1–13

    Google Scholar 

  • Takigawa M (2003) CTGF/Hcs 24 as a multifunctional growth factor for fibroblasts, chondrocytes, and vascular endothelial cells. Drug News Perspect 16:11–21

    Article  CAS  PubMed  Google Scholar 

  • Takigawa M (2005) CTGF/Hcs24/CCN2 as a regeneration factor (“regenerin”) acting on various types of mesenchymal cells. In: Columbus F (ed) Progress in stem cell research. Nova Science, Hauppauge, pp 101–128

    Google Scholar 

  • Takigawa M (2013) CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal 7:191–201

    Article  PubMed  PubMed Central  Google Scholar 

  • Takigawa M (2015) Terminology of CCN1-6 should not be applicable for their fragments and be limited to only full length CCN1-6. J Cell Commun Signal 9(1):81–83

    Article  PubMed  PubMed Central  Google Scholar 

  • Takigawa M (2017) The CCN proteins: an overview. Methods Mol Biol 1489:1–8

    Article  CAS  PubMed  Google Scholar 

  • Takigawa M, Tajima K, Pan H-O, Enomoto M, Kinoshita A, Suzuki F, Takano Y, Mori Y (1989) Establishment of a clonal human chondrosarcoma cell line with cartilage phenotypes. Cancer Res 49:3996–4002

    CAS  PubMed  Google Scholar 

  • Takigawa M, Pan H-O, Kinoshita A, Tajima K, Takano Y (1991) Establishment from a human chondrosarcoma of a new immortal cell line with abilities to form proteoglycan-rich cartilage nodules and to respond to insulin in vitro and high tumorigenicity in vivo. Int J Cancer 48:717–725

  • Takigawa M, Nakanishi T, Kubota S, Nishida T (2003) The role of CTGF/Hcs24/ecogenin in skeletal growth control. J Cell Physiol 194:256–266

    Article  CAS  PubMed  Google Scholar 

  • Tamatani T, Kobayashi H, Tezuka K, Sakamoto S, Suzuki K, Nakanishi T, Takigawa M, Miyano T (1998) Establishment of the enzyme-linked immunosorbent assay for connective tissue growth factor (CTGF) and its detection in the sera of biliary atresia. Biochem Biophys Res Commun 251:748–752

    Article  CAS  PubMed  Google Scholar 

  • Trackman PC, Kantarci A (2015) Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 94(4):540–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ubink I, Verhaar ER, Kranenburg O, Goldschmeding R (2016) A potential role for CCN2/CTGF in aggressive colorectal cancer. J Cell Commun Signal 10(3):223–227

    Article  PubMed  PubMed Central  Google Scholar 

  • Wandji SA, Gadsby JE, Barber JA, Hammond JM (2000) Messenger ribonucleic acids for MAC25 and connective tissue growth factor (CTGF) are inversely regulated during folliculogenesis and early luteogenesis. Endocrinology 141:2648–2657

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Li B, Li C, Cui W, Miao L (2015) Potential renoprotective agents through inhibiting CTGF/CCN2 in diabetic nephropathy. J Diabetes Res 2015:962383

    PubMed  PubMed Central  Google Scholar 

  • Wells JE, Howlett M, Cole CH, Kees UR (2015) Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer. Int J Cancer 137(3):504–511

    Article  CAS  PubMed  Google Scholar 

  • Wong M, Siegrist M, Goodwin K (2003) Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes. Bone 33(4):685–693

    Article  CAS  PubMed  Google Scholar 

  • Yamaai T, Nakanishi T, Asano M, Nawachi K, Yoshimichi G, Ohyama K, Komori T, Sugimoto T, Takigawa M (2005) Gene expression of connective tissue growth factor (CTGF/CCN2) in calcifying tissues of normal and cbfa1-null mutant mice in late stage of embryonic development. J Bone Miner Metab 23(4):280–288

  • Yamashiro T, Fukunaga T, Kobashi N, Kamioka H, Nakanishi T, Takigawa M, Takano-Yamamoto T (2001) Mechanical stimulation induces CTGF expression in rat osteocytes. J Dent Res 80:461–465

    Article  CAS  PubMed  Google Scholar 

  • Yang M, Huang H, Li J, Li D, Wang H (2004) Tyrosine phosphorylation of the LDL receptor-related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation. FASEB J 18(15):1920–1921

  • Yeger H, Perbal B (2016) CCN family of proteins: critical modulators of the tumor cell microenvironment. J Cell Commun Signal 10(3):229–240

    Article  PubMed  PubMed Central  Google Scholar 

  • Yosimichi G, Nakanishi T, Nishida T, Hattori T, Takano-Yamamoto T, Takigawa M (2001) CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen- activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). Eur J Biochem 268:6058–6065

    Article  CAS  PubMed  Google Scholar 

  • Yosimichi G, Kubota S, Nishida T, Kondo S, Yanagita T, Nakao K, Takano-Yamamoto T, Takigawa M (2006) Roles of PKC, PI3K and JNK in multiple transduction of CCN2/CTGF signals in chondrocytes. Bone 38:853–863

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I wish to express my deepest thanks and gratitude to Prof. Bernard Perbal, the president of the International CCN Society for encouraging me to write this historical review. Without Prof. Perbal’s talent and interest in CCN proteins, this field would not be at its present stage. I also greatly respect Prof. Perbal for the launching of the International CCN Society and of the Journal of Cell Communication and Signaling.

Work performed in my previous laboratory, Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences during these past twenty years (1994-2004) had been funded by the programs Grants-in-Aid for Scientific Research (S) twice, (A) once, and (B) six times and four times by Exploratory Research from Japan Society for the Promotion of Sciences. This current work was supported in part by grants from the program Grants-in-Aid for Scientific Research (B) (#JP15H0501419) and for Challenging Research (Exploratory) (#JP17K1975709) from Japan Society for the Promotion of Sciences.

This review is dedicated to all my colleagues who have helped me and participated actively in this exciting field of research.

Author information

Authors and Affiliations

  1. Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Dental School/Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8525, Japan

    Masaharu Takigawa

Authors
  1. Masaharu Takigawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaharu Takigawa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takigawa, M. An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J. Cell Commun. Signal. 12, 253–264 (2018). https://doi.org/10.1007/s12079-017-0414-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-017-0414-6

Keywords

Search

Navigation