Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis
Open accessAbstract
Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc+/−) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline–deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc+/− mice expressed more OPN and developed worse liver fibrosis ( P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis ( P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression ( P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs ( P < 0.05); neutralizing OPN with RNA aptamers attenuated this ( P < 0.05). Conclusion: OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH (Hepatology 2011)
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Cholangiocytes can undergo lipoapoptosis and senescence when exposed to increased saturated fatty acids, releasing DAMPs, SASP factors such as CCL2, and SPP1 that activate HSCs and generate fibrosis.
“Like hepatocytes, cholangiocytes can undergo lipoapoptosis and senescence in the presence of increased saturated fatty acids, which may provoke release of damage-associated molecular patterns, senescence-associated secretory patterns (such as chemokine ligand 2 (CCL2)), and SPP1, which activate HSCs to generate fibrosis (37-40).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [38]
SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model.
“SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model (38, 159).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [38]
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Nonalcoholic Steatohepatitis: A Proposal for Grading and Staging The Histological Lesions
Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A., & Bacon, B. R. (1999) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.1999.01377.x · Cited by 3,907 · see citing works
Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity
Ashkar, S., Weber, G. F., Panoutsakopoulou, V., Sanchirico, M. E., Jansson, M., Zawaideh, S., Rittling, S. R., Denhardt, D. T., Glimcher, M. J., & Cantor, H. (2000) · Science · doi:10.1126/science.287.5454.860 · Cited by 1,125 · see citing works
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis
Feldstein, A. E., Canbay, A., Angulo, P., Taniai, M., Burgart, L. J., Lindor, K. D., & Gores, G. J. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00907-7 · Cited by 1,085 · see citing works
The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease
Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., et al. (2001) · Science · doi:10.1126/science.1062960 · Cited by 829 · see citing works
Osteopontin: role in cell signaling and cancer progression
Rangaswami, H., Bulbule, A., & Kundu, G. C. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.12.005 · Cited by 738 · see citing works
THE INFLUENCE OF THE PROINFLAMMATORY CYTOKINE, OSTEOPONTIN, ON AUTOIMMUNE DEMYELINATING DISEASE
Chabas, D., Baranzini, S. E., Mitchell, D. J., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M. V., Pedotti, R., et al. (2002) · International Conference on Osteopontin and SIBLING Proteins · doi:10.1100/tsw.2002.326 · Cited by 729 · see citing works
Wieckowska, A., Zein, N. N., Yerian, L. M., López, R., McCullough, A. J., & Feldstein, A. E. (2006) · Hepatology · doi:10.1002/hep.21223 · Cited by 668 · see citing works
Kupffer Cell Engulfment of Apoptotic Bodies Stimulates Death Ligand and Cytokine Expression
Canbay, A. E., Feldstein, A. E., Higuchi, H., Werneburg, N., Grambihler, A., Bronk, S. F., & Gores, G. J. (2003) · Hepatology · doi:10.1053/jhep.2003.50472 · Cited by 469 · see citing works
Omenetti, A., Porrello, A., Jung, Y., Yang, L., Popov, Y. V., Choi, S. S., Witek, R. P., Alpini, G. D., Venter, J., VanDongen, H. M. A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35875 · Cited by 342 · see citing works
Self-citationAnimal models of NASH: Getting both pathology and metabolic context right
Larter, C. Z., & Yeh, M. M. (2008) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2008.05543.x · Cited by 337 · see citing works
Fas enhances fibrogenesis in the bile duct ligated mouse: A link between apoptosis and fibrosis
Canbay, A. E., Higuchi, H., Bronk, S. F., Taniai, M., Sebo, T. J., & Gores, G. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.35953 · Cited by 300 · see citing works
Mori, R., Shaw, T. J., & Martin, P. B. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071412 · Cited by 294 · see citing works
Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease
Syn, W.-K., Oo, Y. H., Pereira, T. A., Karaca, G. F., Jung, Y., Omenetti, A., Witek, R. P., Choi, S. S., Guy, C. D., Fearing, C. M., et al. (2010) · Hepatology · doi:10.1002/hep.23599 · Cited by 283 · see citing works
Self-citationSyn, W., Jung, Y., Omenetti, A., Abdelmalek, M. F., Guy, C. D., Yang, L., Wang, J., Witek, R. P., Fearing, C. M., Pereira, T. A., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.06.051 · Cited by 257 · see citing works
Self-citationOsteopontin as a mediator of NKT cell function in T cell-mediated liver diseases.
Diao, H., Kon, S., Iwabuchi, K., Kimura, C., Morimoto, J., Ito, D., Segawa, T., Maeda, M., Hamuro, J., Nakayama, T., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.08.012 · Cited by 226 · see citing works
Choi, S. S., Omenetti, A., Witek, R. P., Moylan, C. A., Syn, W.-K., Jung, Y., Yang, L., Sudan, D. L., Sicklick, J. K., Michelotti, G. A., et al. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00292.2009 · Cited by 219 · see citing works
Self-citationWitek, R. P., Yang, L., Liu, R., Jung, Y., Omenetti, A., Syn, W., Choi, S. S., Cheong, Y., Fearing, C. M., Agboola, K. M., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.09.066 · Cited by 210 · see citing works
Self-citationSahai, A., Malladi, P., Melin-Aldana, H., Green, R. M., & Whitington, P. F. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00002.2004 · Cited by 181 · see citing works
Self-citationSignals from dying hepatocytes trigger growth of liver progenitors
Jung, Y., Witek, R. P., Syn, W., Choi, S. S., Omenetti, A., Premont, R. T., Guy, C. D., & Diehl, A. M. (2010) · Gut · doi:10.1136/gut.2009.204354 · Cited by 161 · see citing works
Self-citationYata, Y., Gotwals, P. J., Koteliansky, V., & Rockey, D. C. (2002) · Hepatology · doi:10.1053/jhep.2002.32673 · Cited by 159 · see citing works
RNA Aptamer Blockade of Osteopontin Inhibits Growth and Metastasis of MDA-MB231 Breast Cancer Cells
Mi, Z., Guo, H., Russell, M. B., Liu, Y., Sullenger, B. A., & Kuo, P. C. (2008) · Molecular Therapy · doi:10.1038/mt.2008.235 · Cited by 157 · see citing works
Self-citationAltered bleomycin-induced lung fibrosis in osteopontin-deficient mice.
Berman, J., Serlin, D., Li, X.-F., Whitley, G., Hayes, J., Rishikof, D., Ricupero, D., Liaw, L., Goetschkes, M., & O'Regan, A. (2004) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00394.2003 · Cited by 135 · see citing works
Das, S., Harris, L. G., Metge, B. J., Liu, S., Riker, A. I., Samant, R. S., & Shevde, L. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.021949 · Cited by 125 · see citing works
Tajiri, K., Shimizu, Y., Tsuneyama, K., & Sugiyama, T. (2009) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0b013e32831bc3d6 · Cited by 122 · see citing works
Ishimura, N., Bronk, S. F., & Gores, G. J. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.01.055 · Cited by 110 · see citing works
Omenetti, A., & Diehl, A. M. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00543.2007 · Cited by 109 · see citing works
Self-citationOsteopontin as two-sided mediator of intestinal inflammation
Heilmann, K., Hoffmann, U., Witte, E., Loddenkemper, C., Sina, C., Schreiber, S., Hayford, C., Holzlbhner, P., Wolk, K., Tchatchou, E., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00428.x · Cited by 92 · see citing works
Lorena, D., Darby, I. A., Gadeau, A., Leen, L. L. S., Rittling, S. R., Pôrto, L. C., Rosenbaum, J., & Desmoulière, A. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.07.024 · Cited by 83 · see citing works
Effects and regulation of osteopontin in rat hepatic stellate cells
Lee, S. H., Seo, G. S., Park, Y. N., Yoo, T. M., & Sohn, D. H. (2004) · Biochemical Pharmacology · doi:10.1016/j.bcp.2004.08.022 · Cited by 81 · see citing works
Whitington, P., Malladi, P., Melín-Aldana, H., Azzam, R., Mack, C., & Sahai, A. (2005) · Pediatric Research · doi:10.1203/01.pdr.0000161414.99181.61 · Cited by 72 · see citing works
Self-citationCorneal wound healing in an osteopontin-deficient mouse.
Miyazaki, K.-I., Okada, Y., Yamanaka, O., Kitano, A., Ikeda, K., Kon, S., Uede, T., Rittling, S., Denhardt, D., Kao, W., et al. (2008) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.07-1007 · Cited by 64 · see citing works
Hepatic stellate cells and fibrosis progression in patients with nonalcoholic fatty liver disease
Feldstein, A. E., Papouchado, B. G., Angulo, P., Sanderson, S., Adams, L. A., & Gores, G. J. (2005) · Clinical Gastroenterology and Hepatology · doi:10.1016/s1542-3565(04)00616-0 · Cited by 60 · see citing works
Role for hedgehog pathway in regulating growth and function of invariant NKT cells
Syn, W., Witek, R. P., Curbishley, S. M., Jung, Y., Choi, S. S., Enrich, B., Omenetti, A., Agboola, K. M., Fearing, C. M., Tilg, H., et al. (2009) · European Journal of Immunology · doi:10.1002/eji.200838890 · Cited by 58 · see citing works
Self-citationSimilarities and Differences in the Pathogenesis of Alcoholic and Nonalcoholic Steatohepatitis
Syn, W., Teaberry, V. S., Choi, S. S., & Diehl, A. M. (2009) · Seminars in Liver Disease · doi:10.1055/s-0029-1214375 · Cited by 56 · see citing works
Self-citationChoi, S. S., Witek, R. P., Yang, L., Omenetti, A., Syn, W., Moylan, C. A., Jung, Y., Karaca, G., Teaberry, V. S., Pereira, T. A., et al. (2010) · Hepatology · doi:10.1002/hep.23649 · Cited by 50 · see citing works
Self-citationHuang, W., Zhu, G., Huang, M., Lou, G., Liu, Y., & Wang, S. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.01.029 · Cited by 49 · see citing works
Fickert, P., Thueringer, A., Moustafa, T., Silbert, D., Gumhold, J., Tsybrovskyy, O., Lebofsky, M., Jaeschke, H., Denk, H., & Trauner, M. A. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2010.61 · Cited by 42 · see citing works
Primary culture of cholangiocytes from normal mouse liver
Yahagi, K., Ishii, M., Kobayashi, K., Ueno, Y., Mano, Y., Niitsuma, H., Igarashi, T., & Toyota, T. (1998) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-998-0106-x · Cited by 35 · see citing works
Morimoto, J., Inobe, M., Kimura, C., Kon, S., Diao, H., Aoki, M., Miyazaki, T., Denhardt, D., Rittling, S., & Uede, T. (2004) · International Immunology · doi:10.1093/intimm/dxh044 · Cited by 35 · see citing works
Impaired angiogenic response in the corneas of mice lacking osteopontin.
Fujita, N., Fujita, S., Okada, Y., Fujita, K., Kitano, A., Yamanaka, O., Miyamoto, T., Kon, S., Uede, T., Rittling, S., et al. (2010) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.09-3420 · Cited by 23 · see citing works
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Tsuchida, T., & Friedman, S. L. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.38 · Cited by 2,909 · see citing works
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784 · see citing works
Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671 · see citing works
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Huby, T., & Gautier, E. L. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00639-3 · Cited by 573 · see citing works
Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis
Wang, X., Zheng, Z., Caviglia, J. M., Corey, K. E., Herfel, T. M., Cai, B., Masia, R., Chung, R. T., Lefkowitch, J. H., Schwabe, R. F., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.016 · Cited by 413 · see citing works
Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Peverill, W., Powell, L. W., & Skoien, R. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058591 · Cited by 380 · see citing works
Moylan, C. A., Pang, H., Dellinger, A. E., Suzuki, A., Garrett, M. E., Guy, C. D., Murphy, S. K., Ashley‐Koch, A. E., Choi, S. S., Michelotti, G. A., et al. (2013) · Hepatology · doi:10.1002/hep.26661 · Cited by 316 · see citing works
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Self-citationUrtasun, R., Lopategi, A., George, J., Leung, T. M., Lu, Y., Wang, X., Ge, X., Fiel, M. I., & Nieto, N. (2011) · Hepatology · doi:10.1002/hep.24701 · Cited by 257 · see citing works
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Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., Meroni, M., Graham, M. J., Yates, K. P., Diehl, A. M., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0344 · Cited by 250 · see citing works
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Weber, C., Kothari, A. N., Wai, P. Y., Li, N. Y., Driver, J., Zapf, M. A. C., Franzen, C. A., Gupta, G. N., Osipo, C., Zlobin, A., et al. (2014) · Oncogene · doi:10.1038/onc.2014.410 · Cited by 228 · see citing works
Self-citationYilmaz, Y. N. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12046 · Cited by 217 · see citing works
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Self-citationPhilips, G., Chan, I. S., Swiderska, M., Schroder, V. T., Guy, C. D., Karaca, G., Moylan, C. A., Venkatraman, T. N., Feuerlein, S., Syn, W., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023943 · Cited by 164 · see citing works
Self-citationKumar, V., Xin, X., Ma, J., Tan, C., Osna, N. A., & Mahato, R. I. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113888 · Cited by 160 · see citing works
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Qian, J., LeSavage, B. L., Hubka, K. M., Ma, C., Natarajan, S., Eggold, J. T., Xiao, Y., Fuh, K. C., Krishnan, V., Enejder, A. M. K., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146186 · Cited by 132 · see citing works
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Lazaro, R. G., Wu, R. P., Lee, S., Zhu, N., Chen, C., French, S. W., Xu, J., Machida, K., & Tsukamoto, H. (2014) · Hepatology · doi:10.1002/hep.27383 · Cited by 120 · see citing works
Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy
Swiderska-Syn, M., Syn, W. K., Xie, G., Krüger, L., Machado, M. V., Karaca, G., Michelotti, G. A., Choi, S. S., Premont, R. T., & Diehl, A. M. (2014) · Gut · doi:10.1136/gutjnl-2013-305962 · Cited by 115 · see citing works
Self-citationOsteopontin—A Master Regulator of Epithelial-Mesenchymal Transition
Kothari, A. N., Arffa, M., Chang, V. A., Blackwell, R. H., Syn, W., Zhang, J., Mi, Z., & Kuo, P. C. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5040039 · Cited by 115 · see citing works
Self-citationSchulien, I., Hockenjos, B., Schmitt-Graeff, A., Perdekamp, M. G., Follo, M., Thimme, R., & Hasselblatt, P. (2019) · Cell Death & Differentiation · doi:10.1038/s41418-018-0239-8 · Cited by 111 · see citing works
Role of Osteopontin in Liver Diseases
Wen, Y., Jeong, S., Xia, Q., & Kong, X. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.16445 · Cited by 109 · see citing works
Osteopontin induces ductular reaction contributing to liver fibrosis
Wang, X., Lopategi, A., Ge, X., Lu, Y., Kitamura, N., Urtasun, R., Leung, T.-M., Fiel, M. I., & Nieto, N. (2014) · Gut · doi:10.1136/gutjnl-2013-306373 · Cited by 108 · see citing works
McGettigan, B. M., McMahan, R. H., Orlicky, D. J., Burchill, M. A., Danhorn, T., Francis, P., Cheng, L. L., Golden‐Mason, L., Jakubzick, C., & Rosen, H. R. (2018) · Hepatology · doi:10.1002/hep.30401 · Cited by 107 · see citing works
Host Regulators of Liver Fibrosis During Human Schistosomiasis
Kamdem, S. D., Moyou‐Somo, R., Brombacher, F., & Nono, J. K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02781 · Cited by 107 · see citing works
Kiefer, F. W., Neschen, S., Pfau, B., Legerer, B., Neuhofer, A., Kahle, M., Hrabé de Angelis, M., Schlederer, M., Mair, M., Kenner, L., et al. (2011) · Diabetologia · doi:10.1007/s00125-011-2170-0 · Cited by 104 · see citing works
Xie, R., & Liu, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.857110 · Cited by 98 · see citing works
Ismail, M. H., & Pinzani, M. (2009) · Saudi Journal of Gastroenterology · doi:10.4103/1319-3767.45072 · Cited by 98 · see citing works
Innate Immunity and Pathogenesis of Biliary Atresia
Ortiz‐Perez, A., Donnelly, B., Temple, H., Tiao, G. M., Bansal, R., & Mohanty, S. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00329 · Cited by 98 · see citing works
Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice
Coombes, J. D., Swiderska‐Syn, M., Dollé, L., Reid, D. T., Eksteen, B., Claridge, L. C., Briones-Orta, M. A., Shetty, S., Oo, Y. H., Riva, A., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-306484 · Cited by 97 · see citing works
Self-citationHuman and experimental evidence supporting a role for osteopontin in alcoholic hepatitis
Morales‐Ibanez, O., Domínguez, M., Ki, S. H., Marcos, M., Chaves, F. J., Nguyen-Khac, É., Houchi, H., Affò, S., Sancho‐Bru, P., Altamirano, J., et al. (2013) · Hepatology · doi:10.1002/hep.26521 · Cited by 97 · see citing works
Pritchett, J. P., Harvey, E., Athwal, V. S., Berry, A. A., Rowe, C., Oakley, F., Moles, A., Mann, D. A., Bobola, N., Sharrocks, A. D., et al. (2012) · Hepatology · doi:10.1002/hep.25758 · Cited by 97 · see citing works
Glass, O., Henao, R., Patel, K., Guy, C. D., Gruss, H. J., Syn, W., Moylan, C. A., Streilein, R. D., Hall, R. P., Diehl, A. M., et al. (2018) · Hepatology Communications · doi:10.1002/hep4.1237 · Cited by 95 · see citing works
Self-citationMaricic, I., Sheng, H., Marrero, I., Seki, E., Kisseleva, T., Chaturvedi, S., Molle, N., Mathews, S., Gao, B., & Kumar, V. (2014) · Hepatology · doi:10.1002/hep.27632 · Cited by 94 · see citing works
Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver
Musso, G., Paschetta, E., Gambino, R., Cassader, M., & Molinaro, F. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.05.006 · Cited by 93 · see citing works
Implication of the Hedgehog pathway in hepatocellular carcinoma
Corte, C. M. D., Viscardi, G., Papaccio, F., Esposito, G., Martini, G., Ciardiello, D., Martinelli, E., Ciardiello, F., & Morgillo, F. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i24.4330 · Cited by 90 · see citing works
Osteopontin: Versatile modulator of liver diseases
Nagoshi, S. (2013) · Hepatology Research · doi:10.1111/hepr.12166 · Cited by 87 · see citing works
Vismodegib Suppresses TRAIL-mediated Liver Injury in a Mouse Model of Nonalcoholic Steatohepatitis
Hirsova, P., Ibrahim, S. H., Bronk, S. F., Yagita∥, H., & Gores, G. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070599 · Cited by 86 · see citing works
Kwon, H., Song, K., Han, C. L., Chen, W., Wang, Y., Dash, S., Lim, K., & Wu, T. (2015) · Hepatology · doi:10.1002/hep.28289 · Cited by 86 · see citing works
Patouraux, S., Bonnafous, S., Voican, C. S., Anty, R., Saint‐Paul, M., Rosenthal‐Allieri, M. A., Agostini, H., Njiké‐Nakseu, M., Barri‐Ova, N., Naveau, S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035612 · Cited by 86 · see citing works
An Overview of Hedgehog Signaling in Fibrosis
Hu, L., Lin, X., Lu, H., Chen, B., & Bai, Y. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.095141 · Cited by 86 · see citing works
Matricellular Protein Periostin Contributes to Hepatic Inflammation and Fibrosis
Huang, Y., Liu, W., Xiao, H., Maitikabili, A., Lin, Q., Wu, T., Huang, Z., Liu, F., Luo, Q., & Ouyang, G. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.11.002 · Cited by 84 · see citing works
Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link?
Targher, G., Lonardo, A., & Rossini, M. (2015) · Journal of Endocrinological Investigation · doi:10.1007/s40618-015-0315-6 · Cited by 84 · see citing works
Yilmaz, Y. N. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2012.05196.x · Cited by 80 · see citing works
Hedgehog signaling in cholangiocytes
Omenetti, A., & Diehl, A. M. (2011) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32834550b4 · Cited by 77 · see citing works
Self-citationCao, L., Fan, X., Jing, W., Liang, Y., Chen, R., Liu, Y., Zhu, M., Jia, R., Wang, H., Zhang, X., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3113 · Cited by 74 · see citing works
Hedgehog Signaling: Implications in Cancers and Viral Infections
Iriana, S., Asha, K., Repak, M., & Sharma-Walia, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031042 · Cited by 73 · see citing works
Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity
Guy, C. D., Suzuki, A., Abdelmalek, M. F., Burchette, J. L., Diehl, A. M., & CRN, F. T. N. (2015) · Hepatology · doi:10.1002/hep.27235 · Cited by 72 · see citing works
Self-citationLocatelli, I., Sutti, S., Vacchiano, M., Bozzola, C., & Albano, E. (2012) · Clinical Science · doi:10.1042/cs20120289 · Cited by 68 · see citing works
Seth, R. K., Kumar, A., Das, S., Kadiiska, M. B., Michelotti, G. A., Diehl, A. M., & Chatterjee, S. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft104 · Cited by 67 · see citing works
Self-citationOsteopontin – A potential biomarker of advanced liver disease
Brůha, R., Vı́tek, L., & Smid, V. (2020) · Annals of Hepatology · doi:10.1016/j.aohep.2020.01.001 · Cited by 66 · see citing works
Ding, J., Li, H., Zhang, L., Zhou, Y., & Wu, J. H. (2021) · Cells · doi:10.3390/cells10010123 · Cited by 64 · see citing works
A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes
Kakisaka, K., Cazanave, S. C., Werneburg, N. W., Razumilava, N., Mertens, J. C., Bronk, S. F., & Gores, G. J. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.05.011 · Cited by 65 · see citing works
Immunological Mechanisms in the Pathophysiology of Non-Alcoholic Steatohepatitis
Vonghia, L., Michielsen, P. P., & Francque, S. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141019867 · Cited by 64 · see citing works
Peripheral signalling involved in energy homeostasis control
Lancha, A., Frühbeck, G., & Gómez‐Ambrosi, J. (2012) · Nutrition Research Reviews · doi:10.1017/s0954422412000145 · Cited by 65 · see citing works
Animal models of NAFLD from the pathologist's point of view
Denk, H., Abuja, P. M., & Zatloukal, K. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.04.024 · Cited by 64 · see citing works
Mechanisms of Disease Progression in NASH
Bohinc, B. N., & Diehl, A. M. (2012) · Clinics in Liver Disease · doi:10.1016/j.cld.2012.05.002 · Cited by 62 · see citing works
Self-citationRegulators of Cholangiocyte Proliferation
Hall, C. M., Sato, K., Wu, N., Zhou, T., Kyritsi, K., Meng, F., Glaser, S. S., & Alpini, G. D. (2016) · Gene Expression · doi:10.3727/105221616x692568 · Cited by 61 · see citing works
The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time
Effendi, W. I., & Nagano, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010171 · Cited by 59 · see citing works
Moayedfard, Z., Sani, F., Alizadeh, A. A., Lankarani, K. B., Zarei, M., & Azarpira, N. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02929-6 · Cited by 59 · see citing works
Evolution of hepatic fibrosis research
Kawada, N. (2011) · Hepatology Research · doi:10.1111/j.1872-034x.2011.00776.x · Cited by 58 · see citing works
The Space of Disse: The Liver Hub in Health and Disease
Sanz-García, C., Fernández-Iglesias, A., Gracia-Sancho, J., Arráez-Aybar, L. A., Nevzorova, Y. A., & Cubero, F. J. (2021) · Livers · doi:10.3390/livers1010002 · Cited by 57 · see citing works
Osteopontin as a Biomarker in Chronic Kidney Disease
Sinha, S. K., Mellody, M., Carpio, M. B., Damoiseaux, R. D., & Nicholas, S. B. (2023) · Biomedicines · doi:10.3390/biomedicines11051356 · Cited by 61 · see citing works
Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis
Coombes, J. D., Choi, S. S., Swiderska‐Syn, M., Manka, P. P., Reid, D. T., Palma, E., Briones-Orta, M. A., Xie, G., Younis, R. L., Kitamura, N., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.028 · Cited by 59 · see citing works
Self-citationLevitsky, J., Baker, T., Jie, C., Ahya, S. N., Levin, M. L., Friedewald, J. J., Al-Saden, P. C., Salomon, D. R., & Abecassis, M. M. (2014) · Hepatology · doi:10.1002/hep.27346 · Cited by 55 · see citing works
Ibrahim, S. H., Gores, G. J., Hirsova, P., Kirby, M., Miles, L., Jaeschke, A., & Kohli, R. (2013) · Liver International · doi:10.1111/liv.12353 · Cited by 54 · see citing works
Moon, H., Cho, K., Shin, S., Kim, D. Y., Han, K., & Ro, S. W. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030581 · Cited by 53 · see citing works
Clinical Utility of Plasma Glypican-3 and Osteopontin as Biomarkers of Hepatocellular Carcinoma
Lee, H. J., Yeon, J. E., Suh, S. J., Lee, S.-J., Yoon, E. L., Kang, K., Yoo, Y. J., Kim, J. H., Seo, Y. S., Yim, H. J., et al. (2014) · Gut and Liver · doi:10.5009/gnl.2014.8.2.177 · Cited by 53 · see citing works
Targeting Pericyte Differentiation as a Strategy to Modulate Kidney Fibrosis in Diabetic Nephropathy
Humphreys, B. D. (2012) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2012.07.009 · Cited by 53 · see citing works
Okazaki, I., Noro, T., Tsutsui, N., Yamanouchi, E., Kuroda, H., Nakano, M., Yokomori, H., & Inagaki, Y. (2014) · Cancers · doi:10.3390/cancers6031220 · Cited by 52 · see citing works
The hedgehog pathway in nonalcoholic fatty liver disease
Machado, M. V., & Diehl, A. M. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1448752 · Cited by 52 · see citing works
Self-citationIntracellular Osteopontin Inhibits Toll-like Receptor Signaling and Impedes Liver Carcinogenesis
Fan, X., He, C., Jing, W., Zhou, X., Chen, R., Cao, L., Zhu, M., Jia, R., Wang, H., Guo, Y., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0615 · Cited by 51 · see citing works
Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes
Steinman, J. B., Salomao, M. A., & Pajvani, U. B. (2021) · Liver International · doi:10.1111/liv.15025 · Cited by 49 · see citing works
Osteopontin is an important mediator of alcoholic liver diseaseviahepatic stellate cell activation
Seth, D. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i36.13088 · Cited by 51 · see citing works
The Hedgehog Signaling Pathway Emerges as a Pathogenic Target
Smelkinson, M. G. (2017) · Journal of Developmental Biology · doi:10.3390/jdb5040014 · Cited by 49 · see citing works
GLP‐1 receptor agonists: effects on the progression of non‐alcoholic fatty liver disease
Liu, J., Wang, G., Jia, Y., & Xu, Y. (2015) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2580 · Cited by 48 · see citing works
Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice
Patouraux, S., Rousseau, D., Rubio, A., Bonnafous, S., Lavallard, V., Lauron, J., Saint-Paul, M. C., Bailly‐Maitre, B., Tran, A., Crénesse, D., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.174 · Cited by 48 · see citing works
Osteopontin promotes collagen I synthesis in hepatic stellate cells by miRNA-129-5p inhibition
Chen, Y., Ou, Y., Dong, J., Yang, G., Zeng, Z., Liu, Y., Liu, B., Li, W., He, X., & Lan, T. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.11.035 · Cited by 48 · see citing works
Self-citationThe critical role of osteopontin (OPN) in fibrotic diseases
Tang, Z., Xia, Z., Wang, X., & Liu, Y. (2023) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2023.08.007 · Cited by 47 · see citing works
- Authors
- Syn, W.-K., Choi, S. S., Liaskou, E., Karaca, G. F., Agboola, K. M., Oo, Y. H., Mi, Z., Pereira, T. A., Zdanowicz, M., Malladi, P., Chen, Y., Moylan, C., Jung, Y., Bhattacharya, S. D., Teaberry, V., Omenetti, A., Abdelmalek, M. F., Guy, C. D., Adams, D. H., Kuo, P. C., Michelotti, G. A., Whitington, P. F., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- University of Birmingham (GB)
- Northwestern University (US)
- Corresponding author
- Syn, Wing-Kin
- Diehl, Anna Mae
- ORCID
- Venue
- Hepatology
- Published
- 2011-01
- Volume
- 53
- Issue
- 1
- Pages
- 106-115
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3025083
- OpenAlex
- W2039567228
- Cited by
- 275
- References
- 40
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 18 · 2023: 18 · 2022: 19 · 2021: 19 · 2020: 13 · 2019: 14 · 2018: 18 · 2017: 16 · 2016: 17 · 2015: 23 · 2014: 25 · 2013: 15 · 2012: 23
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust
- Alberta Innovates - Health Solutions
- National Institutes of Health (1k08dk080980-01a1, 1r01aa014257-01a2)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA014257, 5R01AA14257-5)
- National Institute of General Medical Sciences (R01GM065113)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077794, K08 DK-080980, R01DK053792)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- osteopontin, Hedgehog signaling, nonalcoholic steatohepatitis, liver fibrosis, hepatic stellate cells, Patched1, methionine-choline-deficient diet, cholangiocytes, extracellular matrix, fibrosis progression, RNA aptamers, cyclopamine, sag
- MeSH terms
- Animals, Cell Line, Choline Deficiency, Diet, Fatty Liver, Humans, Liver Cirrhosis, Methionine, Mice, Inbred C57BL, Veratrum Alkaloids, Up-Regulation, Mice, Osteopontin, Hedgehog Proteins, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease
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