Skip to main content
SpringerLink
Log in

Gremlin is a key pro-fibrogenic factor in chronic pancreatitis

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The current study aims to identify the pro-fibrogenic role of Gremlin, an endogenous antagonist of bone morphogenetic proteins (BMPs) in chronic pancreatitis (CP). CP is a highly debilitating disease characterized by progressive pancreatic inflammation and fibrosis that ultimately leads to exocrine and endocrine dysfunction. While transforming growth factor (TGF)-β is a known key pro-fibrogenic factor in CP, the TGF-β superfamily member BMPs exert an anti-fibrogenic function in CP as reported by our group recently. To investigate how BMP signaling is regulated in CP by BMP antagonists, the mouse CP model induced by cerulein was used. During CP induction, TGF-β1 messenger RNA (mRNA) increased 156-fold in 2 weeks, a BMP antagonist Gremlin 1 (Grem1) mRNA levels increased 145-fold at 3 weeks, and increases in Grem1 protein levels correlated with increases in collagen deposition. Increased Grem1 was also observed in human CP pancreata compared to normal. Grem1 knockout in Grem1 +/− mice revealed a 33.2 % reduction in pancreatic fibrosis in CP compared to wild-type littermates. In vitro in isolated pancreatic stellate cells, TGF-β induced Grem1 expression. Addition of the recombinant mouse Grem1 protein blocked BMP2-induced Smad1/5 phosphorylation and abolished BMP2’s suppression effects on TGF-β-induced collagen expression. Evidences presented herein demonstrate that Grem1, induced by TGF-β, is pro-fibrogenic by antagonizing BMP activity in CP.

Key messages

  • Gremlin is upregulated in human chronic pancreatitis and a mouse CP model in vivo.

  • Deficiency of Grem1 in mice attenuates pancreatic fibrosis under CP induction in vivo.

  • TGF-β induces Gremlin mRNA and protein expression in pancreatic stellate cells in vitro.

  • Gremlin blocks BMP2 signaling and function in pancreatic stellate cells in vitro.

  • This study discloses a pro-fibrogenic role of Gremlin by antagonizing BMP activity in chronic pancreatitis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Fagenholz PJ, Fernandez-del Castillo C, Harris NS, Pelletier AJ, Camargo CA Jr (2007) Direct medical costs of acute pancreatitis hospitalizations in the United States. Pancreas 35:302–307

    Article  PubMed  Google Scholar 

  2. Jupp J, Fine D, Johnson CD (2010) The epidemiology and socioeconomic impact of chronic pancreatitis. Best Pract Res Clin Gastroenterol 24:219–231

    Article  PubMed  Google Scholar 

  3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921

    Article  CAS  PubMed  Google Scholar 

  4. Warshaw AL, Banks PA, Fernandez-Del Castillo C (1998) AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 115:765–776

    Article  CAS  PubMed  Google Scholar 

  5. Omary MB, Lugea A, Lowe AW, Pandol SJ (2007) The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117:50–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Kinoshita K, Iimuro Y, Otogawa K, Saika S, Inagaki Y, Nakajima Y, Kawada N, Fujimoto J, Friedman SL, Ikeda K (2007) Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 56:706–714

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Myllarniemi M, Lindholm P, Ryynanen MJ, Kliment CR, Salmenkivi K, Keski-Oja J, Kinnula VL, Oury TD, Koli K (2008) Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis. Am J Respir Crit Care Med 177:321–329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Yang YL, Liu YS, Chuang LY, Guh JY, Lee TC, Liao TN, Hung MY, Chiang TA (2009) Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-beta receptors. Endocrinology 150:727–740

    Article  CAS  PubMed  Google Scholar 

  9. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968

    Article  CAS  PubMed  Google Scholar 

  10. Gao X, Cao Y, Staloch DA, Gonzales MG, Aronson JF, Chao C, Hellmich MR, Ko TC (2014) Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One 9:e89114

    Article  PubMed Central  PubMed  Google Scholar 

  11. Gao X, Cao Y, Yang W, Duan C, Aronson JF, Rastellini C, Chao C, Hellmich MR, Ko TC (2013) BMP2 inhibits TGF-beta-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol 304:G804–G813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Khokha MK, Hsu D, Brunet LJ, Dionne MS, Harland RM (2003) Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34:303–307

    Article  CAS  PubMed  Google Scholar 

  13. Dolan V, Murphy M, Sadlier D, Lappin D, Doran P, Godson C, Martin F, O’Meara Y, Schmid H, Henger A et al (2005) Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy. Am J Kidney Dis 45:1034–1039

    Article  CAS  PubMed  Google Scholar 

  14. Boers W, Aarrass S, Linthorst C, Pinzani M, Elferink RO, Bosma P (2006) Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins. J Biol Chem 281:16289–16295

    Article  CAS  PubMed  Google Scholar 

  15. Namkoong H, Shin SM, Kim HK, Ha SA, Cho GW, Hur SY, Kim TE, Kim JW (2006) The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer 6:74

    Article  PubMed Central  PubMed  Google Scholar 

  16. Walsh DW, Roxburgh SA, McGettigan P, Berthier CC, Higgins DG, Kretzler M, Cohen CD, Mezzano S, Brazil DP, Martin F (2008) Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochim Biophys Acta 1782:10–21

    Article  CAS  PubMed  Google Scholar 

  17. Zhang Q, Shi Y, Wada J, Malakauskas SM, Liu M, Ren Y, Du C, Duan H, Li Y, Zhang Y (2010) In vivo delivery of Gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. PLoS One 5, e11709. doi:10.1371/journal.pone.0011709

    Article  PubMed Central  PubMed  Google Scholar 

  18. Roxburgh SA, Kattla JJ, Curran SP, O’Meara YM, Pollock CA, Goldschmeding R, Godson C, Martin F, Brazil DP (2009) Allelic depletion of grem1 attenuates diabetic kidney disease. Diabetes 58:1641–1650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Cao Y, Chen L, Zhang W, Liu Y, Papaconstantinou HT, Bush CR, Townsend CM Jr, Thompson EA, Ko TC (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:G28–G38

    Article  CAS  PubMed  Google Scholar 

  20. Feng XP, Yi H, Li MY, Li XH, Yi B, Zhang PF, Li C, Peng F, Tang CE, Li JL et al (2010) Identification of biomarkers for predicting nasopharyngeal carcinoma response to radiotherapy by proteomics. Cancer Res 70:3450–3462

    Article  CAS  PubMed  Google Scholar 

  21. Zhou WH, Tang F, Xu J, Wu X, Feng ZY, Li HG, Lin DJ, Shao CK, Liu Q (2011) Aberrant upregulation of 14-3-3o expression serves as an inferior prognostic biomarker for gastric cancer. BMC Cancer 11:397

    Article  PubMed Central  PubMed  Google Scholar 

  22. Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M, Nasir A, Rodriguez BA, Liu J, Yan PS, Quackenbush J et al (2008) Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res 68:1786–1796

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Perides G, Tao X, West N, Sharma A, Steer ML (2005) A mouse model of ethanol dependent pancreatic fibrosis. Gut 54:1461–1467

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115:421–432

    Article  CAS  PubMed  Google Scholar 

  25. Sha G, Zhang Y, Zhang C, Wan Y, Zhao Z, Li C, Lang J (2009) Elevated levels of gremlin-1 in eutopic endometrium and peripheral serum in patients with endometriosis. Fertil Steril 91:350–358

    Article  CAS  PubMed  Google Scholar 

  26. Wellbrock J, Sheikhzadeh S, Oliveira-Ferrer L, Stamm H, Hillebrand M, Keyser B, Klokow M, Vohwinkel G, Bonk V, Otto B et al (2014) Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. PLoS One 9:e104742

    Article  PubMed Central  PubMed  Google Scholar 

  27. Cahill E, Costello CM, Rowan SC, Harkin S, Howell K, Leonard MO, Southwood M, Cummins EP, Fitzpatrick SF, Taylor CT et al (2012) Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation 125:920–930

    Article  CAS  PubMed  Google Scholar 

  28. Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE et al (2006) Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A 103:14842–14847

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Mulvihill MS, Kwon YW, Lee S, Fang LT, Choi H, Ray R, Kang HC, Mao JH, Jablons D, Kim IJ (2012) Gremlin is overexpressed in lung adenocarcinoma and increases cell growth and proliferation in normal lung cells. PLoS One 7:e42264

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Karagiannis GS, Treacy A, Messenger D, Grin A, Kirsch R, Riddell RH, Diamandis EP (2014) Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts. Mol Oncol 8:1240–1252

    Article  CAS  PubMed  Google Scholar 

  31. Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer-Hofer K, Zammataro L, Presta M (2010) Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116:3677–3680

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank E. Figueroa, S. Schuenke, and K. Martin in the Department of Surgery, University of Texas Medical Branch for the manuscript and figure preparation and submission. This study was supported by a grant from the National Institutes of Health (P01 DK35608).

Conflict of interest

The authors declare that they have no competing interests.

Author information

Author notes

    Authors and Affiliations

    1. Department of Surgery, The University of Texas Health Science Center - Houston, 6431 Fannin Street, MSB4.608, Houston, TX, 77030, USA

      Dustin Staloch, Xuxia Gao, Ka Liu, Meihua Xu, Xueping Feng, Yanna Cao & Tien C. Ko

    2. Department of General Practice, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

      Xuxia Gao

    3. Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China

      Meihua Xu & Xueping Feng

    4. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

      Judith F. Aronson

    5. Department of Pharmacology, University of Texas Medical Branch, Galveston, TX, USA

      Miriam Falzon

    6. Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

      George H. Greeley, Cristiana Rastellini, Celia Chao, Mark R. Hellmich, Yanna Cao & Tien C. Ko

    Authors
    1. Dustin Staloch
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xuxia Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ka Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Meihua Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xueping Feng
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Judith F. Aronson
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Miriam Falzon
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. George H. Greeley
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Cristiana Rastellini
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Celia Chao
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Mark R. Hellmich
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Yanna Cao
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Tien C. Ko
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yanna Cao.

    Additional information

    Dustin Staloch, Xuxia Gao and Ka Liu contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Staloch, D., Gao, X., Liu, K. et al. Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. J Mol Med 93, 1085–1093 (2015). https://doi.org/10.1007/s00109-015-1308-9

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-015-1308-9

    Keywords

    Search

    Navigation