Gastroenterology and Hepatology
PTHrP/PTHR1 and TGF-β Levels Are Inversely Associated in Liver Regeneration
Abstract
Background. Transforming growth factor (TGF)-β provides growth control in liver regeneration. We have recently demonstrated that TGF-β induced parathyroid hormone-related protein (PTHrP) expression and secretion, and PTHrP mediated TGF-β-induced apoptosis in liver cells. However, whether PTHrP signaling pathway is altered during liver regeneration is unknown. Therefore we used a murine hepatectomy model in this study and tested the hypothesis that both PTHrP and TGF-β signaling pathways are upregulated during liver regeneration.
Methods. Swiss Webster mice received 70% hepatectomy or sham operation and euthanized at different time points post-surgery for analyses. Liver regeneration was determined by liver/body weight and proliferating cell nuclear antigen (PCNA) staining. mRNA levels of TGF-β1, TGF-β receptors, PTHrP, and PTHrP receptor 1 (PTHR1) were measured by real-time quantitative PCR. Protein levels of TGF-β1 were measured by ELISA and PTHrP and PTHR1 were measured by Western blotting.
Results. After 70% hepatectomy, the liver regeneration began at 24 hours and was restored to 82% of original liver mass at day 7. TGF-β1 and its receptor levels increased at 24 and 48 hours after hepatectomy, while PTHrP levels decreased at 12 hours and PTHR1 levels decreased at 12, 24 and 48 hours after hepatectomy. The levels of these molecules returned to similar levels as that in sham animals thereafter.
Conclusion. We demonstrated that an upregulation of the TGF-β and its receptors were associated with a down-regulation of PTHrP/PTHR1 expression during liver regeneration, which may contribute to hepatocyte proliferation and regeneration after hepatectomy.
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Bissell, D. M., Wang, S. S., Jarnagin, W. R., & Roll, F. J. (1995). Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest, 96(1), 447-455. doi: 10.1172/JCI118055
Braun, L., Mead, J. E., Panzica, M., Mikumo, R., Bell, G. I., & Fausto, N. (1988). Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A, 85(5), 1539-1543.
Breitkopf, K., Godoy, P., Ciuclan, L., Singer, M. V., & Dooley, S. (2006). TGF-beta/Smad signaling in the injured liver. Z Gastroenterol, 44(1), 57-66. doi: 10.1055/s-2005-858989
Cao, Y., Chen, L., Zhang, W., Liu, Y., Papaconstantinou, H. T., Bush, C. R., . . . Ko, T. C. (2007). Identification of apoptotic genes mediating TGF-beta/Smad3-induced cell death in intestinal epithelial cells using a genomic approach. Am J Physiol Gastrointest Liver Physiol, 292(1), G28-38. doi: 00437.2005 [pii]10.1152/ajpgi.00437.2005
Cao, Y., Zhang, W., Gao, X., Zhang, G., Falzon, M., Townsend, C. M., Jr., . . . Ko, T. C. (2013). PTHrP is a novel mediator for TGF-beta-induced apoptosis. Regul Pept, 184C, 40-46. doi: 10.1016/j.regpep.2013.03.024
Fausto, N. (2004). Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology, 39(6), 1477-1487. doi: 10.1002/hep.20214
Fausto, N., & Riehle, K. J. (2005). Mechanisms of liver regeneration and their clinical implications. J Hepatobiliary Pancreat Surg, 12(3), 181-189. doi: 10.1007/s00534-005-0979-y
Funk, J. L., Moser, A. H., Grunfeld, C., & Feingold, K. R. (1997). Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response. Endocrinology, 138(7), 2665-2673.
Gao, X., Cao, Y., Staloch, D. A., Gonzales, M. A., Aronson, J. F., Chao, C., . . . Ko, T. C. (2014). Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One, 9(2), e89114. doi: 10.1371/journal.pone.0089114
Gao, X., Cao, Y., Yang, W., Duan, C., Aronson, J. F., Rastellini, C., . . . Ko, T. C. (2013). BMP2 inhibits TGF-beta-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol, 304(9), G804-813. doi: 10.1152/ajpgi.00306.2012
Greene, A. K., & Puder, M. (2003). Partial hepatectomy in the mouse: technique and perioperative management. J Invest Surg, 16(2), 99-102. doi: WHTYD43KD3C3G3RG [pii]
Heldin, C. H., Miyazono, K., & ten Dijke, P. (1997). TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 390(6659), 465-471. doi: 10.1038/37284
Houck, K. A., & Michalopoulos, G. K. (1989). Altered responses of regenerating hepatocytes to norepinephrine and transforming growth factor type beta. J Cell Physiol, 141(3), 503-509. doi: 10.1002/jcp.1041410308
Jackson, L. N., Larson, S. D., Silva, S. R., Rychahou, P. G., Chen, L. A., Qiu, S., . . . Evers, B. M. (2008). PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol, 294(6), G1401-1410. doi: 00062.2008 [pii] 10.1152/ajpgi.00062.2008
Jakowlew, S. B., Mead, J. E., Danielpour, D., Wu, J., Roberts, A. B., & Fausto, N. (1991). Transforming growth factor-beta (TGF-beta) isoforms in rat liver regeneration: messenger RNA expression and activation of latent TGF-beta. Cell Regul, 2(7), 535-548.
Kakonen, S. M., Selander, K. S., Chirgwin, J. M., Yin, J. J., Burns, S., Rankin, W. A., . . . Guise, T. A. (2002). Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem, 277(27), 24571-24578. doi: 10.1074/jbc.M202561200M202561200 [pii]
Karkampouna, S., Goumans, M. J., Ten Dijke, P., Dooley, S., & Kruithof-de Julio, M. (2015). Inhibition of TGFbeta type I receptor activity facilitates liver regeneration upon acute CCl intoxication in mice. Arch Toxicol. doi: 10.1007/s00204-014-1436-y
Karkampouna, S., Ten Dijke, P., Dooley, S., & Julio, M. K. (2012). TGFbeta signaling in liver regeneration. Curr Pharm Des, 18(27), 4103-4113. doi: CPD-EPUB-20120522-28 [pii]
Li, H., Seitz, P. K., Selvanayagam, P., Rajaraman, S., & Cooper, C. W. (1996). Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2). Endocrinology, 137(6), 2367-2374.
Lindemann, R. K., Ballschmieter, P., Nordheim, A., & Dittmer, J. (2001). Transforming growth factor beta regulates parathyroid hormone-related protein expression in MDA-MB-231 breast cancer cells through a novel Smad/Ets synergism. J Biol Chem, 276(49), 46661-46670. doi: 10.1074/jbc.M105816200M105816200 [pii]
Liska, V., Treska, V., Mirka, H., Kobr, J., Sykora, R., Skalicky, T., . . . Holubec, L. (2012). Inhibition of transforming growth factor beta-1 augments liver regeneration after partial portal vein ligation in a porcine experimental model. Hepatogastroenterology, 59(113), 235-240. doi: 10.5754/hge10116
Massague, J. (1998). TGF-beta signal transduction. Annu Rev Biochem, 67, 753-791. doi: 10.1146/annurev.biochem.67.1.753
Michalopoulos, G. K., & DeFrances, M. C. (1997). Liver regeneration. Science, 276(5309), 60-66.
Murray, N. R., Davidson, L. A., Chapkin, R. S., Clay Gustafson, W., Schattenberg, D. G., & Fields, A. P. (1999). Overexpression of protein kinase C betaII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. J Cell Biol, 145(4), 699-711.
Philbrick, W. M., Wysolmerski, J. J., Galbraith, S., Holt, E., Orloff, J. J., Yang, K. H., . . . Stewart, A. F. (1996). Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev, 76(1), 127-173.
Qiu, T., Wu, X., Zhang, F., Clemens, T. L., Wan, M., & Cao, X. (2010). TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat Cell Biol, 12(3), 224-234. doi: 10.1038/ncb2022
Shimizu, M., Hara, A., Okuno, M., Matsuno, H., Okada, K., Ueshima, S., . . . Mori, H. (2001). Mechanism of retarded liver regeneration in plasminogen activator-deficient mice: impaired activation of hepatocyte growth factor after Fas-mediated massive hepatic apoptosis. Hepatology, 33(3), 569-576.
Zhong, Z., Tsukada, S., Rehman, H., Parsons, C. J., Theruvath, T. P., Rippe, R. A., . . . Lemasters, J. J. (2010). Inhibition of transforming growth factor-beta/Smad signaling improves regeneration of small-for-size rat liver grafts. Liver Transpl, 16(2), 181-190. doi: 10.1002/lt.21966
DOI: http://dx.doi.org/10.3968/gh.v2i1.6175
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