Abstract
CCN family proteins 2 and 3 (CCN2 and CCN3) belong to the CCN family of proteins, all having a high level of structural similarity. It is widely known that CCN2 is a profibrotic molecule that mediates the development of fibrotic disorders in many different tissues and organs. In contrast, CCN3 has been recently suggested to act as an anti-fibrotic factor in several tissues. This CCN3 action was shown earlier to be exerted by the repression of the CCN2 gene expression in kidney tissue, whereas different findings were obtained for liver cells. Thus, the molecular action of CCN3 yielding its anti-fibrotic effect is still controversial. Here, using a general model of fibrosis, we evaluated the effect of CCN3 overexpression on the gene expression of all of the CCN family members, as well as on that of fibrotic marker genes. As a result, repression of CCN2 gene expression was modest, while type I collagen and α-smooth muscle actin gene expression was prominently repressed. Interestingly, not only CCN2, but also CCN4 gene expression showed a decrease upon CCN3 overexpression. These findings indicate that fibrotic gene induction is under the control of a complex molecular network conducted by CCN family members functioning together.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Borkham-Kamphorst E, van Roeyen CR, Van de Leur E, Floege J, Weiskirchen R (2012) CCN3/NOV small interfering RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic fat storing cell line CFSC. J Cell Commun Signal 6:11–25
Brigstock DR, Goldschmeding R, Katsube K, LamSCT LLF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H (2003) Proposal for a unified CCN nomenclature. Mol Pathol 56:127–128
Canalis E (2007) Nephroblastoma overexpressed (Nov) is a novel bone morphogenetic protein antagonist. Ann N Y Acad Sci 1116:50–58
Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783
Colston JT, de la Rosa SD, Koehler M, Gonzales K, Mestril R, Freeman GL, Bailey SR, Chandrasekar B (2007) Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. Am J Physiol Heart Circ Physiol 293:H1839–H1846
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
Hoshijima M, Hattori T, Aoyama E, Nishida T, Yamashiro T, Takigawa M (2012) Role of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes. FEBS J 279:3584–3597
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
Janune D, Kubota S, Nishida T, Kawaki H, Perbal B, Iida S, Takigawa M (2011) Novel effects of CCN3 that may direct the differentiation of chondrocytes. FEBS Lett 585:3033–3040
Kawaki H, Kubota S, Suzuki A, Lazar N, Yamada T, Matsumura T, Ohgawara T, Maeda T, Perbal B, Lyons KM, Takigawa M (2008) Cooperative regulation of chondrocyte differentiation by CCN2 and CCN3 shown by a comprehensive analysis of the CCN family proteins in cartilage. J Bone Miner Res 23:1751–1764
Kawaki H, Kubota S, Suzuki A, Suzuki M, Kohsaka K, Hoshi K, Fujii T, Lazar N, Ohgawara T, Maeda T, Perbal B, Takano-Yamamoto T, Takigawa M (2011) Differential roles of CCN family proteins during osteoblast differentiation: Involvement of Smad and MAPK signaling pathways. Bone 49:975–989
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 Part A 14:1089–1098
Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O (2009) WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119:772–787
Kubota S (2012) CCN2 and orofacial tissue development and remodeling. Jpn Dent Sci Rev. in press, doi:10.1016/j.jdsr.2012.02.002
Kubota S, Takigawa M (2007) Role of CCN2/CTGF/Hcs24 in bone growth. Int Rev Cytol 257:1–41
Kubota S, Takigawa M (2011) The role of CCN2 in cartilage and bone development. J Cell Commun Signal 5:209–217
Leask A (2009) Yin and Yang: CCN3 inhibits the pro-fibrotic effects of CCN2. J Cell Commun Signal 3:161–162
Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810
Leask A, Parapuram SK, Shi-Wen X, Abraham DJ (2009) Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease? J Cell Commun Signal 3:89–94
Maeda A, Nishida T, Aoyama E, Kubota S, Lyons KM, Kuboki T, Takigawa M (2009) CCN family 2/connective tissue growth factor modulates BMP signalling as a signal conductor, which action regulates the proliferation and differentiation of chondrocytes. J Biochem 145:207–216
Ono M, Kubota S, Fujisawa T, Sonoyama W, Kawaki H, Akiyama K, Shimono K, Oshima M, Nishida T, Yoshida Y, Suzuki K, Takigawa M, Kuboki T (2008) Promotion of hydroxyapatite-associated, stem cell-based bone regeneration by CCN2. Cell Transplant 17:231–240
Perbal B, Takigawa M (2005) CCN Protein -A new family of cell growth and differentiation regulators-. Imperial College Press, London, pp 1–311
Planque N, Long Li C, Saule S, Bleau AM, Perbal B (2006) Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins. J Cell Biochem 99:105–116
Riser BL, Najmabadi F, Perbal B, Peterson DR, Rambow JA, Riser ML, Sukowski E, Yeger H, Riser SC (2009) CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. Am J Pathol 174:1725–1734
Sabbah M, Prunier C, Ferrand N, Megalophonos V, Lambein K, De Wever O, Nazaret N, Lachuer J, Dumont S, Redeuilh G (2011) CCN5, a novel transcriptional repressor of the transforming growth factor β signaling pathway. Mol Cell Biol 31:1459–1469
Smerdel-Ramoya A, Zanotti S, Deregowski V, Canalis E (2008) Connective tissue growth factor enhances osteoblastogenesis in vitro. J Biol Chem 283:22690–22699
Yoon PO, Lee MA, Cha H, Jeong MH, Kim J, Jang SP, Choi BY, Jeong D, Yang DK, Hajjar RJ, Park WJ (2010) The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis. J Mol Cell Cardiol 49:294–303
Acknowledgments
This study was supported by grants from the program Grants-in-aid for Scientific Research (S)(B) to M.T. and (C) to S.K. from the Japan Society for the Promotion of Science and by a research grant from Terumo Life Science Foundation to S.K. The authors would like to thank Matthew L. Springer at UCSF, who gave us the Ecotropic Phoenix cell line.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Abd El Kader, T., Kubota, S., Janune, D. et al. Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family. J. Cell Commun. Signal. 7, 11–18 (2013). https://doi.org/10.1007/s12079-012-0180-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12079-012-0180-4