The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling
Open accessAbstract
Unlabelled Cysteine-rich protein 61 (CCN1/CYR61) is a CCN (CYR61, CTGF (connective tissue growth factor), and NOV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-β signaling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. Conclusion In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.
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There is evidence of a beneficial effect of both pro-senescent and anti-senescent approaches, depending on context.
“There is evidence of a beneficial effect of both pro-senescent and anti-senescent approaches, depending on context.”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [301]
A pro-senescent effect may be desirable in treating cancer, renal, liver and cutaneous fibrosis.
“A pro-senescent effect may be desirable in treating cancer [295,296,297], renal, liver and cutaneous fibrosis [298,299,300,301].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [301]
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Senescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Kamata, H., Honda, S.-I., Maeda, S., Chang, L., Hirata, H., & Karin, M. (2005) · Cell · doi:10.1016/j.cell.2004.12.041 · Cited by 1,792 · see citing works
Jun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb2070 · Cited by 998 · see citing works
Gressner, A. M., & Weiskirchen, R. (2006) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2006.tb00292.x · Cited by 718 · see citing works
Self-citationDiversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.
Bornstein, P. (1995) · The Journal of cell biology · doi:10.1083/jcb.130.3.503 · Cited by 666 · see citing works
All in the CCN family: essential matricellular signaling modulators emerge from the bunker
Leask, A., & Abraham, D. (2006) · Journal of Cell Science · doi:10.1242/jcs.03270 · Cited by 653 · see citing works
Peer Bork, B. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80155-n · Cited by 623 · see citing works
Evolving challenges in hepatic fibrosis
Friedman, S. L. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.97 · Cited by 582 · see citing works
Knittel, T. E., Kobold, D., Saile, B., Grundmann, A., Neubauer, K., Piscaglia, F., & Ramadori, G. P. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70407-5 · Cited by 338 · see citing works
CCN1/CYR61: the very model of a modern matricellular protein
Lau, L. F. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0778-3 · Cited by 338 · see citing works
Li, Z., Dranoff, J. A., Chan, E. P., Uemura, M., Sévigny, J., & Wells, R. G. (2007) · Hepatology · doi:10.1002/hep.21792 · Cited by 336 · see citing works
Kim, K.-H., Chen, C.-C., Monzon, R. I., & Lau, L. F. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00049-13 · Cited by 261 · see citing works
The synthesis of proteoglycans in fat-storing cells of rat liver
Schäfer, S., Zerbe, O., & Gressner, A. M. (1987) · Hepatology · doi:10.1002/hep.1840070411 · Cited by 258 · see citing works
Cellular senescence controls fibrosis in wound healing
Jun, J.-I., & Lau, L. F. (2010) · Aging · doi:10.18632/aging.100201 · Cited by 255 · see citing works
Tuchweber, B., Desmoulière, A., Bochaton‐Piallat, M., Rubbia‐Brandt, L., & Gabbiani, G. (1996) · PubMed · Cited by 205 · see citing works
Protein and its function based on a subcellular localization
Ćmielová, J., & Řezáčová, M. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23296 · Cited by 165 · see citing works
Beaussier, M., Wendum, D., Schiffer, E. R. C., Dumont, S., Rey, C., Lienhart, A., & Housset, C. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700513 · Cited by 160 · see citing works
Fehrenbach, H., Weiskirchen, R., Kasper, M., & Gressner, A. M. (2001) · Hepatology · doi:10.1053/jhep.2001.28788 · Cited by 154 · see citing works
Self-citationSawtell, N. M., & Lessard, J. L. (1989) · The Journal of Cell Biology · doi:10.1083/jcb.109.6.2929 · Cited by 150 · see citing works
Borkham‐Kamphorst, E., Herrmann, J., Stoll, D., Treptau, J., Gressner, A. M., & Weiskirchen, R. (2004) · Laboratory Investigation · doi:10.1038/labinvest.3700094 · Cited by 147 · see citing works
Self-citationCytotoxicity of TNFα is regulated by integrin‐mediated matrix signaling
Chen, C., Young, J. L., Monzon, R. I., Chen, N., Todorović, V., & Lau, L. F. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601596 · Cited by 143 · see citing works
Peribiliary myofibroblasts in biliary type liver fibrosis
Kinnman, N. (2002) · Frontiers in bioscience · doi:10.2741/a790 · Cited by 139 · see citing works
The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts
Todorovicç, V., Chen, C.-C., Hay, N., & Lau, L. F. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200504015 · Cited by 132 · see citing works
Temporal Expression of the Chondrogenic and Angiogenic Growth Factor CYR61 During Fracture Repair
Hadjiargyrou, M., Ahrens, W., & Rubin, C. T. (2000) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2000.15.6.1014 · Cited by 110 · see citing works
Hilfiker-Kleiner, D., Kaminski, K., Kaminska, A., Fuchs, M., Klein, G., Podewski, E., Grote, K., Kiian, I., Wollert, K. C., Hilfiker, A., et al. (2004) · Circulation · doi:10.1161/01.cir.0000127952.90508.9d · Cited by 110 · see citing works
Borkham‐Kamphorst, E., Kovalenko, E., van Roeyen, C. R. C., Gaßler, N., Bomble, M., Ostendorf, T., Floege, J., Gressner, A. M., & Weiskirchen, R. (2008) · Laboratory Investigation · doi:10.1038/labinvest.2008.71 · Cited by 106 · see citing works
Self-citationAthanasopoulos, A. N., Schneider, D., Keiper, T., Alt, V., Pendurthi, U. R., Liegibel, U. M., Sommer, U., Nawroth, P. P., Kasperk, C., & Chavakis, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705200200 · Cited by 99 · see citing works
Rojkind, M., Novikoff, P. M., Greenwel, P., Rubin, J. B., Rojas-Valencia, L., de Carvalho, A. C. C., Stockert, R. J., Spray, D. C., Hertzberg, E. L., & Wolkoff, A. W. (1995) · PubMed Central · Cited by 86 · see citing works
Arias, M., Sauer-Lehnen, S., Treptau, J., Janoschek, N., Theuerkauf, I., Buettner, R., Gressner, A. M., & Weiskirchen, R. (2003) · BMC Gastroenterology · doi:10.1186/1471-230x-3-29 · Cited by 81 · see citing works
Self-citationTargeted Mutagenesis of the Angiogenic Protein CCN1 (CYR61)
Leu, S.-J., Chen, N., Chen, C.-C., Todorović, V., Bai, T., Juric, V., Liu, Y., Yan, G., Lam, S. C.-T., & Lau, L. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407850200 · Cited by 72 · see citing works
Juric, V., Chen, C.-C., & Lau, L. F. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00064-09 · Cited by 70 · see citing works
Meurer, S. K., Tihaa, L., Borkham‐Kamphorst, E., & Weiskirchen, R. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.12.002 · Cited by 64 · see citing works
Self-citationWeiskirchen, R., & Bister, K. (1993) · PubMed · Cited by 57 · see citing works
Self-citationIsolation of Primary Rat Liver Fibroblasts
Kruglov, E. A., Jain, D., & Dranoff, J. A. (2002) · Journal of Investigative Medicine · doi:10.2310/6650.2002.33431 · Cited by 54 · see citing works
Juric, V., Chen, C.-C., & Lau, L. F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031303 · Cited by 52 · see citing works
Chen, C., & Lau, L. F. (2010) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-009-0080-4 · Cited by 47 · see citing works
Guyot, C., Combe, C., Balabaud, C. P., Bioulac‐Sage, P., & Desmoulière, A. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.08.013 · Cited by 43 · see citing works
Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney
Sawai, K., Mukoyama, M., Mori, K., Kasahara, M., Koshikawa, M., Yokoi, H., Yoshioka, T., Ogawa, Y., Sugawara, A., Nishiyama, H., et al. (2007) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00205.2007 · Cited by 33 · see citing works
CCN proteins in normal and injured liver
Weiskirchen, R. (2010) · Frontiers in bioscience · doi:10.2741/3832 · Cited by 23 · see citing works
Self-citationGrzeszkiewicz, T. M. (2002) · Endocrinology · doi:10.1210/en.143.4.1441 · Cited by 23 · see citing works
Borkham‐Kamphorst, E., Huss, S., de Leur, E. V., Haas, U., & Weiskirchen, R. (2012) · Liver International · doi:10.1111/j.1478-3231.2012.02837.x · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
Hepatic stellate cells as key target in liver fibrosis
Higashi, T., Friedman, S. L., & Hoshida, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.007 · Cited by 1,485 · see citing works
Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies
Musso, G., Cassader, M., & Gambino, R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.3 · Cited by 415 · see citing works
Jun, J.-I., & Lau, L. F. (2018) · Journal of Clinical Investigation · doi:10.1172/jci93563 · Cited by 348 · see citing works
Tag, C. G., Sauer-Lehnen, S., Weiskirchen, S., Borkham‐Kamphorst, E., Tolba, R. H., Tacke, F., & Weiskirchen, R. (2015) · Journal of Visualized Experiments · doi:10.3791/52438 · Cited by 325 · see citing works
Self-citationLiver Fibrosis: From Pathogenesis to Novel Therapies
Weiskirchen, R., & Tacke, F. (2016) · Digestive Diseases · doi:10.1159/000444556 · Cited by 157 · see citing works
Self-citationTGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis
Ren, L.-L., Miao, H., Wang, Y.-N., Liu, F., Li, P., & Zhao, Y.-Y. (2023) · Aging and disease · doi:10.14336/ad.2023.0222 · Cited by 139 · see citing works
Hepatoprotective and Anti-fibrotic Agents: It's Time to Take the Next Step
Weiskirchen, R. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00303 · Cited by 112 · see citing works
Self-citationCCN1 induces hepatic ductular reaction through integrin αvβ5–mediated activation of NF-κB
Kim, K.-H., Chen, C.-C., Alpini, G., & Lau, L. F. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79327 · Cited by 109 · see citing works
Weiskirchen, R., Weiskirchen, S., & Tacke, F. (2018) · F1000Research · doi:10.12688/f1000research.14841.1 · Cited by 105 · see citing works
Self-citationDysfunction of Hair Follicle Mesenchymal Progenitors Contributes to Age-Associated Hair Loss
Shin, W., Rosin, N. L., Sparks, H. D., Sinha, S., Rahmani, W. M., Sharma, N. C., Workentine, M., Abbasi, S., Labit, E., Stratton, J. A., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.03.019 · Cited by 101 · see citing works
Targeting Senescent Cells in Fibrosis: Pathology, Paradox, and Practical Considerations
Schafer, M. J., Haak, A. J., Tschumperlin, D. J., & LeBrasseur, N. K. (2018) · Current Rheumatology Reports · doi:10.1007/s11926-018-0712-x · Cited by 104 · see citing works
The cytokines of pulmonary fibrosis: Much learned, much more to learn
Luzina, I. G., Todd, N. W., Sundararajan, S., & Atamas, S. P. (2014) · Cytokine · doi:10.1016/j.cyto.2014.11.008 · Cited by 90 · see citing works
The matricellular protein CCN1 in tissue injury repair
Kim, K., Won, J. H., Cheng, N., & Lau, L. F. (2018) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-018-0450-x · Cited by 87 · see citing works
Wan, Y., Meng, F., Wu, N., Zhou, T., Venter, J. K., Francis, H., Kennedy, L. L., Glaser, T., Bernuzzi, F., Invernizzi, P., et al. (2017) · Hepatology · doi:10.1002/hep.29138 · Cited by 90 · see citing works
Redox mechanisms in age-related lung fibrosis
Kurundkar, A., & Thannickal, V. J. (2016) · Redox Biology · doi:10.1016/j.redox.2016.06.005 · Cited by 88 · see citing works
Short-term gain, long-term pain: the senescence life cycle and cancer
Chan, A. S. L., & Narita, M. (2019) · Genes & Development · doi:10.1101/gad.320937.118 · Cited by 80 · see citing works
Kurundkar, A., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.-M., Zmijewski, J. W., & Thannickal, V. J. (2016) · The FASEB Journal · doi:10.1096/fj.201500173 · Cited by 83 · see citing works
Stochastic non-enzymatic modification of long-lived macromolecules - A missing hallmark of aging
Fedintsev, A., & Moskalev, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101097 · Cited by 81 · see citing works
The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins
Tuieng, R. J., Cartmell, S. H., Kirwan, C., & Sherratt, M. J. (2021) · Cells · doi:10.3390/cells10113041 · Cited by 85 · see citing works
Induction of experimental obstructive cholestasis in mice
Tag, C., Weiskirchen, S., Hittatiya, K., Tacke, F., Tolba, R., & Weiskirchen, R. (2015) · Laboratory Animals · doi:10.1177/0023677214567748 · Cited by 79 · see citing works
Self-citationCellular senescence: a view throughout organismal life
von Kobbe, C. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2879-8 · Cited by 69 · see citing works
Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis
Linden, M. A., Sheldon, R. D., Meers, G. M.-E., Ortinau, L. C., Morris, E. M., Booth, F. W., Kanaley, J. A., Vieira‐Potter, V. J., Sowers, J. R., Ibdah, J. A., et al. (2016) · The Journal of Physiology · doi:10.1113/jp272235 · Cited by 68 · see citing works
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Jun, J.-I., & Lau, L. F. (2016) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-016-0359-1 · Cited by 68 · see citing works
Fibroblast—Extracellular Matrix Interactions in Tissue Fibrosis
Frangogiannis, N. G. (2016) · Current Pathobiology Reports · doi:10.1007/s40139-016-0099-1 · Cited by 61 · see citing works
Chan, Y.-T., Wang, N., Tan, H. Y., Li, S., & Feng, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00548 · Cited by 62 · see citing works
Lipocalin-2 (LCN2) regulates PLIN5 expression and intracellular lipid droplet formation in the liver
Asimakopoulou, A., Borkham‐Kamphorst, E., Henning, M., Yagmur, E., Gaßler, N., Liedtke, C., Berger, T., Mak, T. W., & Weiskirchen, R. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.07.017 · Cited by 61 · see citing works
Self-citationTherapeutic pro-fibrogenic signaling pathways in fibroblasts
Cannito, S., Novo, E., & Parola, M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.05.017 · Cited by 60 · see citing works
CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis
Borkham‐Kamphorst, E., Steffen, B. T., de Leur, E. V., Haas, U., Tihaa, L., Friedman, S. L., & Weiskirchen, R. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.10.013 · Cited by 55 · see citing works
Self-citationZoppi, N., Chiarelli, N., Binetti, S., Ritelli, M., & Colombi, M. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.01.005 · Cited by 49 · see citing works
Antifibrotics in chronic liver disease: tractable targets and translational challenges
Ramachandran, P., & Henderson, N. C. (2016) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(16)30110-8 · Cited by 51 · see citing works
MKL1 is an epigenetic modulator of TGF-β induced fibrogenesis
Fan, Z., Hao, C., Li, M., Dai, X., Qin, H., Li, J., Xu, H., Wu, X., Zhang, L., Fang, M., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.07.013 · Cited by 47 · see citing works
The role of cellular senescence in aging through the prism of Koch-like criteria
Yanai, H., & Fraifeld, V. E. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2017.10.004 · Cited by 45 · see citing works
Tang, B., Liu, Y., Zhang, J., Lü, M., & Wang, H. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114920 · Cited by 45 · see citing works
Emerging role of CCN family proteins in fibrosis
Sun, C., Zhang, H., & Liu, X. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30171 · Cited by 40 · see citing works
Ma, M., Long, Q., Chen, F., Zhang, T., & Wang, W. (2019) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2019.10.007 · Cited by 39 · see citing works
Feng, M., Peng, H., Yao, R., Zhang, Z., Mao, G., Yu, H., & Qiu, Y. (2020) · Bone · doi:10.1016/j.bone.2020.115522 · Cited by 38 · see citing works
Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease
Liedtke, C., Nevzorova, Y. A., Luedde, T., Zimmermann, H. W., Kroy, D. C., Strnad, P., Berres, M., Bernhagen, J., Tacke, F., Nattermann, J., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2021.814496 · Cited by 40 · see citing works
Self-citationZoppi, N., Chiarelli, N., Ritelli, M., & Colombi, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19040982 · Cited by 37 · see citing works
Yang, R., Chen, Y., & Chen, D. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.7880 · Cited by 33 · see citing works
Roberts, D. D., Kaur, S., & Isenberg, J. S. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7140 · Cited by 33 · see citing works
Borkham‐Kamphorst, E., Meurer, S. K., de Leur, E. V., Haas, U., Tihaa, L., & Weiskirchen, R. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.03.012 · Cited by 32 · see citing works
Self-citationLabrousse-Arias, D., Martı́nez-Ruiz, A., & Calzada, M. J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7275 · Cited by 31 · see citing works
Li, Z., Wu, W., Zhao, C., Zhao, C., Zhang, X., Yang, Z., Pan, J., & Si, W. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3356 · Cited by 31 · see citing works
Marinkovic, M., Dai, Q., Gonzalez, A. O., Tran, O. N., Block, T. J., Harris, S. E., Salmon, A. B., Yeh, C., Dean, D. D., & Chen, X. (2022) · Matrix Biology · doi:10.1016/j.matbio.2022.06.004 · Cited by 30 · see citing works
Li, Y., Lua, I., French, S. W., & Asahina, K. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00257.2015 · Cited by 29 · see citing works
Fischer, A. G., Elliott, E. M., Brittian, K. R., Garrett, L. T., Sadri, G., Aebersold, J., Singhal, R. A., Nong, Y., Leask, A., Jones, S. P., et al. (2024) · Matrix Biology · doi:10.1016/j.matbio.2024.08.001 · Cited by 28 · see citing works
Umbaugh, D. S., Nguyen, N. T., Smith, S. H., Ramachandran, A., & Jaeschke, H. (2024) · Toxicology · doi:10.1016/j.tox.2024.153804 · Cited by 26 · see citing works
Early to Phase II drugs currently under investigation for the treatment of liver fibrosis
Hauff, P., Gottwald, U., & Ocker, M. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.997874 · Cited by 26 · see citing works
Mechanobiology and the extracellular matrix in pulmonary fibrosis
Ganzleben, I., & Medoff, B. D. (2025) · iScience · doi:10.1016/j.isci.2025.113993 · Cited by 27 · see citing works
Tsou, P., Khanna, D., & Sawalha, A. H. (2019) · Arthritis & Rheumatology · doi:10.1002/art.40890 · Cited by 23 · see citing works
Luo, M., Cai, X., Yan, D., Liu, X., & Guo, S. (2020) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2020.04.006 · Cited by 23 · see citing works
Borkham‐Kamphorst, E., Steffen, B. T., de Leur, E. V., Haas, U., & Weiskirchen, R. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.07.005 · Cited by 22 · see citing works
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Peng, L., Agogo, G. O., Guo, J., & Yan, M. (2019) · Neuropeptides · doi:10.1016/j.npep.2019.101941 · Cited by 21 · see citing works
Chen, X., Di, Y., Zhang, Y., Yang, H., & Wang, Y. (2015) · Drug Design Development and Therapy · doi:10.2147/dddt.s79782 · Cited by 21 · see citing works
The potential role of senescence in limiting fibrosis caused by aging
Meng, X., Wang, H., Song, X., Clifton, A. C., & Xiao, J. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29313 · Cited by 19 · see citing works
Transcriptome changes in stages of non-alcoholic fatty liver disease
Aljabban, J., Rohr, M., Syed, S. A., Khorfan, K., Borkowski, V. J., Aljabban, H., Segal, M., Mukhtar, M., Mohammed, M., Panahiazar, M., et al. (2022) · World Journal of Hepatology · doi:10.4254/wjh.v14.i7.1382 · Cited by 18 · see citing works
Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats
Vaidya, R., Zambrano, R. A. P., Hummler, J., Luo, S., Duncan, M. R., Young, K. C., Lau, L. F., & WU, S. M. (2017) · Pediatric Research · doi:10.1038/pr.2017.160 · Cited by 18 · see citing works
Katsuyama, Y., Tsuboi, T., Taira, N., Yoshioka, M., & Masaki, H. (2016) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2016.03.002 · Cited by 17 · see citing works
Borkham‐Kamphorst, E., Steffen, B. T., de Leur, E. V., Tihaa, L., Haas, U., Woitok, M. M., Meurer, S. K., & Weiskirchen, R. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.07.006 · Cited by 17 · see citing works
Self-citationThe multifunctional protein CCN1/CYR61: Bridging physiology and disease
Kerek, R., Awad, J. S., Bassam, M., Hajjar, C., Ghantous, F., Rizk, K., & Rima, M. (2025) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2025.104969 · Cited by 14 · see citing works
Jiang, L., Fang, P., Weemhoff, J. L., Apte, U. M., & Pritchard, M. T. (2016) · BioMed Research International · doi:10.1155/2016/4918798 · Cited by 12 · see citing works
WISP3 prevents fibroblast–myofibroblast transdifferentiation in NRK-49F cells
Yang, Y., Ma, J., Lu, J., Wang, H., & Zhao, Y. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.01.005 · Cited by 12 · see citing works
Ménard, A., Nader, N. A., Levasseur, A., St‐Jean, G., Roy, M. L. G.-L., Boerboom, D., Benoit‐Biancamano, M., & Boyer, A. (2020) · Endocrinology · doi:10.1210/endocr/bqaa052 · Cited by 12 · see citing works
Ren, J., Wang, X., Parry, S. N., Yee, C., Gorrell, M. D., McLennan, S. V., & Twigg, S. M. (2022) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-022-00667-1 · Cited by 11 · see citing works
Scheri, K. C., Liang, X., Dalal, V., Poole, I. C. L., Varga, J., & Hayashida, T. (2022) · JCI Insight · doi:10.1172/jci.insight.160977 · Cited by 10 · see citing works
Seleem, A. A., & Hussein, B. H. M. (2018) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13191 · Cited by 10 · see citing works
Matricellular Proteins and Organ Fibrosis
Prakoura, N., & Chatziantoniou, C. (2017) · Current Pathobiology Reports · doi:10.1007/s40139-017-0138-6 · Cited by 9 · see citing works
CYR61/CCN1: A novel mediator of redox response in corneal stromal cells of keratoconus
Liu, X., Zhang, X., Li, Q., Wei, C., Guo, X., Zhao, L., Liu, T., Bao, Q., Dou, S., Seitz, B., et al. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110093 · Cited by 8 · see citing works
Wang, Z., Lu, L., Gu, T., Hou, L., Du, L., Zhang, Y., Zhang, Y., Xu, Q., & Chen, G. (2020) · Gene · doi:10.1016/j.gene.2020.145194 · Cited by 8 · see citing works
Xega, V., Alami, T., & Liu, J. (2023) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-023-00765-8 · Cited by 7 · see citing works
Zhao, J., Yue, P., Mi, N., Li, M., Fu, W., Zhang, X., Gao, L., Bai, M., Tian, L., Jiang, N., et al. (2024) · Medical Review · doi:10.1515/mr-2024-0029 · Cited by 7 · see citing works
Zong, D.-W., Guo, C., Cheng, H., Hu, H.-T., Xiao, J., & Li, H. (2016) · Asian Pacific Journal of Tropical Medicine · doi:10.1016/j.apjtm.2016.01.011 · Cited by 6 · see citing works
Zhang, Y., Wu, H., Luo, H., Luo, Y., & Huang, C. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12852 · Cited by 5 · see citing works
Borkham‐Kamphorst, E., Meurer, S. K., & Weiskirchen, R. (2023) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-023-00757-8 · Cited by 5 · see citing works
Self-citationCCN1 expression is regulated by mechanical stimuli in tendons
Leong, N. L., Greskovich, K. E., Blommer, J. M., & Jiang, J. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.04.058 · Cited by 4 · see citing works
Ocular Safety of Intravitreal Connective Tissue Growth Factor Neutralizing Antibody
Motevasseli, T., Daftarian, N., Kanavi, M. R., Ahmadieh, H., Bagheri, A., Hosseini, S. B., Ansari, S., & Soheili, Z. (2017) · Current Eye Research · doi:10.1080/02713683.2017.1297996 · Cited by 4 · see citing works
Esposito, G., Balzamino, B. O., Stigliano, E., Biamonte, F., Urbani, A., & Micera, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-81040-x · Cited by 4 · see citing works
[The effect of deep branches of cervical nerve on motorial function of trapezius muscle].
Wang, F., Wen, Y., & Li, L. (2003) · PubMed · Cited by 4 · see citing works
CCN1 in hepatobiliary injury repair
Kim, K., & Lau, L. F. (2015) · Oncotarget · doi:10.18632/oncotarget.6079 · Cited by 4 · see citing works
Senescence Programs Shape the Chronic Wound Microenvironment
Shvedova, M., Cho, M., Eyckmans, J., & Roh, D. S. (2026) · Advances in Wound Care · doi:10.1177/21621918261441046 · Cited by 3 · see citing works
CYR61 improves muscle force recreation in a rabbit trauma model
Frey, S. P., Yorumazel, B., Hölscher-Doht, S., Eden, L., Schütze, N., Meffert, R. H., & Jansen, H. (2019) · Technology and Health Care · doi:10.3233/thc-191635 · Cited by 3 · see citing works
Schade, M., Sanabria, J. A., Modarresi, M., Gillon, B., Hunter, Z., Fannin, J. C., Mallick, A., Brunengraber, H., & Sanabria, J. R. (2018) · IntechOpen eBooks · doi:10.5772/intechopen.71659 · Cited by 3 · see citing works
Kordes, C., Spitzhorn, L., Bohndorf, M., Ncube, A., Thimm, C., Erichsen, L., Wruck, W., & Adjaye, J. (2025) · Stem Cells and Development · doi:10.1177/15473287251388416 · Cited by 2 · see citing works
CCN1: a SASPy protein that plays multifaceted roles in fibrogenesis
Leask, A. (2025) · Matrix Biology · doi:10.1016/j.matbio.2025.11.007 · Cited by 2 · see citing works
Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy
Hosseini, N., Elshazly, A. M., Byers, H. A., Ward, M. A., Brooks, A. N., Vangala, J. R., & Radhakrishnan, S. K. (2026) · iScience · doi:10.1016/j.isci.2026.115056 · Cited by 2 · see citing works
Gündel, B., Liu, X., Pfützenreuter, A.-M., Engelsberger, V., Weiskirchen, R., Löhr, M. J., & Heuchel, R. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179369 · Cited by 2 · see citing works
Self-citationThe Role of Senescence in Hepatic Diseases
Pacheco-Rivera, R., Arellanes‐Robledo, J., de León, M. C. G., Shibayama, M., & Serrano‐Luna, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804274-8.00023-0 · Cited by 2 · see citing works
Matricellular Proteins and Organ Fibrosis
Prakoura, N., & Chatziantoniou, C. (2017) · Current Pathobiology Reports · doi:10.1007/s40139-017-0130-1 · Cited by 2 · see citing works
Interconnection Between Cellular Senescence, Regeneration and Ageing in Salamanders
Yu, Q., & Yun, M. H. (2020) · Healthy ageing and longevity · doi:10.1007/978-3-030-44903-2_3 · Cited by 2 · see citing works
Circadian clock regulation of myofibroblast fate
Tsoneva, Y., Velikova, T. V., & Nikolaev, G. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.111774 · Cited by 1 · see citing works
Luo, M., Cai, X., Liu, X., Yan, D., & Guo, S. (2022) · Medical Research Archives · doi:10.18103/mra.v10i11.3341 · Cited by 1 · see citing works
Weiskirchen, R. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00239.2015 · Cited by 1 · see citing works
Self-citationOxidative Mechanisms in Liver Senescence and Regeneration
Marongiu, F., Serra, M. P., & Laconi, E. (2015) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-3-319-15539-5_3
Grazioli, S., & Matute‐Bello, G. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00265.2015
Is Senescence Important in Hepatic Diseases?
Pacheco-Rivera, R., Arellanes‐Robledo, J., & Serrano‐Luna, J. (2017) · InTech eBooks · doi:10.5772/intechopen.68587
Precision Medicine Approach to Improving Reconstructive Surgery Outcomes for Breast Cancer Survivors
Degen, K. E. (2018) · VTechWorks (Virginia Tech)
Dionne, S., Restellini, S., Koenekoop, J., Escribano, P. S., Piccirillo, C. A., Charlebois, P., Liberman, A. S., Stein, B., Duchatellier, C. F., & Seidman, E. G. (2019) · F1000Research · doi:10.12688/f1000research.13906.1
Senotherapeutics: Experimental therapy of cellular senescence
Justice, J. N., Niedernhofer, L. J., & Orr, M. E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00012-3
- Authors
- Borkham-Kamphorst, E., Schaffrath, C., Van de Leur, E., Haas, U., Tihaa, L., Meurer, S. K., Nevzorova, Y. A., Liedtke, C., & Weiskirchen, R.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Corresponding author
- Weiskirchen, Ralf
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 1843
- Issue
- 5
- Pages
- 902-914
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2001252458
- Cited by
- 105
- References
- 41
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 9 · 2019: 7 · 2018: 13 · 2017: 14 · 2016: 13 · 2015: 12 · 2014: 4
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Funders
- Faculty of Medicine, RWTH-Aachen University
- Deutsche Forschungsgemeinschaft (SFB/TRR57 P13)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- CYR61, liver fibrosis, hepatic stellate cells, reactive oxygen species, cellular senescence, apoptosis, TGF-beta signaling, type I collagen, bile duct ligation, antifibrotic therapy, adenoviral gene transfer, extracellular matrix
- MeSH terms
- Animals, Male, Signal Transduction, Transforming Growth Factor beta, Cellular Senescence, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Rats, Cysteine-Rich Protein 61, Myofibroblasts
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