An investigation of the equine epidermal growth factor system during hyperinsulinemic laminitis.
Abstract: Equine laminitis is a disease of the digital epidermal lamellae typified by epidermal cell proliferation and structural collapse. Most commonly the disease is caused by hyperinsulinemia, although the pathogenesis is incompletely understood. Insulin can activate the epidermal growth factor (EGF) system in other species and the present study tested the hypothesis that upregulation of EGF receptor (EGFR) signalling is a key factor in laminitis pathophysiology. First, we examined lamellar tissue from healthy Standardbred horses and those with induced hyperinsulinemia and laminitis for EGFR distribution and quantity using immunostaining and gene expression, respectively. Phosphorylation of EGFR was also quantified. Next, plasma EGF concentrations were compared in healthy and insulin-infused horses, and in healthy and insulin-dysregulated ponies before and after feeding. The EGFR were localised to the secondary epidermal lamellae, with stronger staining in parabasal, rather than basal, cells. No change in EGFR gene expression occurred with laminitis, although the receptor showed some phosphorylation. No difference was seen in EGF concentrations in horses, but in insulin-dysregulated ponies mean, post-prandial EGF concentrations were almost three times higher than in healthy ponies (274 ± 90 vs. 97.4 ± 20.9 pg/mL, P = 0.05). Although the EGFR does not appear to play a major pathogenic role in hyperinsulinemic laminitis, the significance of increased EGF in insulin-dysregulated ponies deserves further investigation.
Publication Date: 2019-12-05 PubMed ID: 31805097PubMed Central: PMC6894753DOI: 10.1371/journal.pone.0225843Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research explores the relationship between the epidermal growth factor system and equine laminitis, a disease usually caused by hyperinsulinemia. The study specifically tests whether an increase in epidermal growth factor receptor signalling plays a part in developing the disease, with the results suggesting further investigation is needed.
Introduction
- The research focuses on equine laminitis, a disease that affects the hooves of horses, specifically the digital epidermal lamellae structure. This disease is mostly brought about by an excessive amount of insulin (hyperinsulinemia).
- The association between the disease and hyperinsulinemia is not well-understood. Insulin has been observed to influence the epidermal growth factor (EGF) system in other species. The EGF system involves the epidermal growth factor receptor (EGFR), which the researchers believe can play a critical role in the progression of laminitis.
Methodology
- Researchers first observed lamellar tissue taken from healthy Standardbred horses. Similar observations were made on horses, which were artificially induced with hyperinsulinemia and laminitis.
- The researchers utilized immunostaining and gene expression methods to determine the EGFR distribution and quantity. They also quantified the level of phosphorylation of the EGFR.
- They further analyzed plasma EGF concentrations and compared the levels before and after feeding in healthy horses, insulin-infused horses, and insulin-dysregulated ponies.
Results
- The observations found EGFR localized in the secondary epidermal lamellae with more potent stains in parabasal cells compared to basal cells.
- No significant change was seen in the gene expression of EGFR in relation to laminitis. However, some phosphorylation of the receptor was observed.
- No difference was observed regarding EGF concentrations in horses. However, in insulin-dysregulated ponies, mean post-feeding EGF concentrations were seen to nearly triple compared to those in healthy ponies.
Conclusion
- The study concludes that EGFR does not seem to significantly contribute to the pathological progression of hyperinsulinemic laminitis.
- However, the observable increase of EGF in insulin-dysregulated ponies indicates a possible association or role in the disease pathophysiology, suggesting further studies to deepen our understanding of this connection.
Cite This Article
APA
de Laat MA, Spence RJ, Sillence MN, Pollitt CC.
(2019).
An investigation of the equine epidermal growth factor system during hyperinsulinemic laminitis.
PLoS One, 14(12), e0225843.
https://doi.org/10.1371/journal.pone.0225843 Publication
Researcher Affiliations
- Earth, Environmental and Biological Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
- Earth, Environmental and Biological Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
- Earth, Environmental and Biological Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
- School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
MeSH Terms
- Animals
- Epidermal Growth Factor / blood
- Epidermal Growth Factor / metabolism
- ErbB Receptors / genetics
- ErbB Receptors / metabolism
- Foot Diseases / blood
- Foot Diseases / veterinary
- Gene Dosage
- Gene Expression Regulation
- Hoof and Claw / pathology
- Horse Diseases / blood
- Horse Diseases / metabolism
- Horses / blood
- Hyperinsulinism / blood
- Hyperinsulinism / complications
- Insulin / metabolism
- Phosphorylation
Conflict of Interest Statement
The authors have declared that no competing interests exist.
References
This article includes 50 references
- Sloet van Oldruitenborgh-Oosterbaan MM. Laminitis in the horse: a review.. Vet Q 1999 Oct;21(4):121-7.
- Karikoski NP, Horn I, McGowan TW, McGowan CM. The prevalence of endocrinopathic laminitis among horses presented for laminitis at a first-opinion/referral equine hospital.. Domest Anim Endocrinol 2011 Oct;41(3):111-7.
- Asplin KE, Sillence MN, Pollitt CC, McGowan CM. Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies.. Vet J 2007 Nov;174(3):530-5.
- de Laat MA, McGowan CM, Sillence MN, Pollitt CC. Equine laminitis: induced by 48 h hyperinsulinaemia in Standardbred horses.. Equine Vet J 2010 Mar;42(2):129-35.
- Patterson-Kane JC, Karikoski NP, McGowan CM. Paradigm shifts in understanding equine laminitis.. Vet J 2018 Jan;231:33-40.
- de Laat MA, van Eps AW, McGowan CM, Sillence MN, Pollitt CC. Equine laminitis: comparative histopathology 48 hours after experimental induction with insulin or alimentary oligofructose in standardbred horses.. J Comp Pathol 2011 Nov;145(4):399-409.
- Burns TA, Watts MR, Weber PS, McCutcheon LJ, Geor RJ, Belknap JK. Laminar inflammatory events in lean and obese ponies subjected to high carbohydrate feeding: Implications for pasture-associated laminitis.. Equine Vet J 2015 Jul;47(4):489-93.
- de Laat MA, Patterson-Kane JC, Pollitt CC, Sillence MN, McGowan CM. Histological and morphometric lesions in the pre-clinical, developmental phase of insulin-induced laminitis in Standardbred horses.. Vet J 2013 Mar;195(3):305-12.
- Karikoski NP, McGowan CM, Singer ER, Asplin KE, Tulamo RM, Patterson-Kane JC. Pathology of Natural Cases of Equine Endocrinopathic Laminitis Associated With Hyperinsulinemia.. Vet Pathol 2015 Sep;52(5):945-56.
- Nanayakkara SN, Rahnama S, Harris PA, Anderson ST, de Laat MA, Bailey S, Sillence MN. Characterization of insulin and IGF-1 receptor binding in equine liver and lamellar tissue: implications for endocrinopathic laminitis.. Domest Anim Endocrinol 2019 Jan;66:21-26.
- Burns TA, Watts MR, Weber PS, McCutcheon LJ, Geor RJ, Belknap JK. Distribution of insulin receptor and insulin-like growth factor-1 receptor in the digital laminae of mixed-breed ponies: an immunohistochemical study.. Equine Vet J 2013 May;45(3):326-32.
- de Laat MA, Pollitt CC, Kyaw-Tanner MT, McGowan CM, Sillence MN. A potential role for lamellar insulin-like growth factor-1 receptor in the pathogenesis of hyperinsulinaemic laminitis.. Vet J 2013 Aug;197(2):302-6.
- Kullmann A, Weber PS, Bishop JB, Roux TM, Norby B, Burns TA, McCutcheon LJ, Belknap JK, Geor RJ. Equine insulin receptor and insulin-like growth factor-1 receptor expression in digital lamellar tissue and insulin target tissues.. Equine Vet J 2016 Sep;48(5):626-32.
- Baskerville CL, Chockalingham S, Harris PA, Bailey SR. The effect of insulin on equine lamellar basal epithelial cells mediated by the insulin-like growth factor-1 receptor.. PeerJ 2018;6:e5945.
- Shin M, Yang EG, Song HK, Jeon H. Insulin activates EGFR by stimulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells.. BMB Rep 2015 Jun;48(6):342-7.
- Chong MP, Barritt GJ, Crouch MF. Insulin potentiates EGFR activation and signaling in fibroblasts.. Biochem Biophys Res Commun 2004 Sep 17;322(2):535-41.
- Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN. Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.. Mol Syst Biol 2009;5:256.
- Grosenbaugh DA, Hood DM, Amoss MS Jr, Williams JD. Characterisation and distribution of epidermal growth factor receptors in equine hoof wall laminar tissue: comparison of normal horses and horses affected with chronic laminitis.. Equine Vet J 1991 May;23(3):201-6.
- Fitzgerald DM, Walsh DM, Sillence MN, Pollitt CC, de Laat MA. Insulin and incretin responses to grazing in insulin-dysregulated and healthy ponies.. J Vet Intern Med 2019 Jan;33(1):225-232.
- Obel N. Studies on the Histopathology of Acute Laminitis. Dissertation: Almqvist and Wiksells Boktryckeri AB, Uppsala, Sweden; 1948.
- Fitzgerald DM, Walsh DM, Sillence MN, Pollitt CC, de Laat MA. Insulin and incretin responses to grazing in insulin-dysregulated and healthy ponies.. J Vet Intern Med 2019 Jan;33(1):225-232.
- Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction.. BMC Bioinformatics 2012 Jun 18;13:134.
- de Laat MA, Fitzgerald DM, Sillence MN, Spence RJ. Glucagon-like peptide-2: A potential role in equine insulin dysregulation.. Equine Vet J 2018 Nov;50(6):842-847.
- Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A. Fiji: an open-source platform for biological-image analysis.. Nat Methods 2012 Jun 28;9(7):676-82.
- Hauschild G, Geburek F, Gosheger G, Eveslage M, Serrano D, Streitbürger A, Johannlükens S, Menzel D, Mischke R. Short term storage stability at room temperature of two different platelet-rich plasma preparations from equine donors and potential impact on growth factor concentrations.. BMC Vet Res 2017 Jan 5;13(1):7.
- Trypsteen W, Vynck M, De Neve J, Bonczkowski P, Kiselinova M, Malatinkova E, Vervisch K, Thas O, Vandekerckhove L, De Spiegelaere W. ddpcRquant: threshold determination for single channel droplet digital PCR experiments.. Anal Bioanal Chem 2015 Jul;407(19):5827-34.
- Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life.. Annu Rev Pharmacol Toxicol 2004;44:195-217.
- Liu R, Li W, Tao B, Wang X, Yang Z, Zhang Y, Wang C, Liu R, Gao H, Liang J, Yang W. Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance.. Nat Commun 2019 Mar 1;10(1):991.
- Majumder A, Ray S, Banerji A. Epidermal growth factor receptor-mediated regulation of matrix metalloproteinase-2 and matrix metalloproteinase-9 in MCF-7 breast cancer cells.. Mol Cell Biochem 2019 Feb;452(1-2):111-121.
- Šelemetjev S, Bartolome A, Išić Denčić T, Đorić I, Paunović I, Tatić S, Cvejić D. Overexpression of epidermal growth factor receptor and its downstream effector, focal adhesion kinase, correlates with papillary thyroid carcinoma progression.. Int J Exp Pathol 2018 Apr;99(2):87-94.
- Karikoski NP, Patterson-Kane JC, Asplin KE, McGowan TW, McNutt M, Singer ER, McGowan CM. Morphological and cellular changes in secondary epidermal laminae of horses with insulin-induced laminitis.. Am J Vet Res 2014 Feb;75(2):161-8.
- Grosenbaugh DA, Amoss MS, Hood DM, Williams JD. EGF receptor-binding activity in the urine of normal horses and horses affected by chronic laminitis.. Domest Anim Endocrinol 1990 Jul;7(3):277-89.
- Jeffrey SC, Murray MJ, Eichorn ES. Distribution of epidermal growth factor receptor (EGFr) in normal and acute peptic-injured equine gastric squamous epithelium.. Equine Vet J 2001 Nov;33(6):562-9.
- Hansen LA, Woodson RL 2nd, Holbus S, Strain K, Lo YC, Yuspa SH. The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors.. Cancer Res 2000 Jul 1;60(13):3328-32.
- Schneider MR, Werner S, Paus R, Wolf E. Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology.. Am J Pathol 2008 Jul;173(1):14-24.
- Macdonald-Obermann JL, Pike LJ. Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation.. J Biol Chem 2014 Sep 19;289(38):26178-26188.
- Gross SM, Rotwein P. Mapping growth-factor-modulated Akt signaling dynamics.. J Cell Sci 2016 May 15;129(10):2052-63.
- Cheon SS, Nadesan P, Poon R, Alman BA. Growth factors regulate beta-catenin-mediated TCF-dependent transcriptional activation in fibroblasts during the proliferative phase of wound healing.. Exp Cell Res 2004 Feb 15;293(2):267-74.
- Valiathan R, Ashman M, Asthana D. Effects of Ageing on the Immune System: Infants to Elderly.. Scand J Immunol 2016 Apr;83(4):255-66.
- Evanson JR, Guyton MK, Oliver DL, Hire JM, Topolski RL, Zumbrun SD, McPherson JC, Bojescul JA. Gender and age differences in growth factor concentrations from platelet-rich plasma in adults.. Mil Med 2014 Jul;179(7):799-805.
- de Laat MA, Sillence MN, Reiche DB. Phenotypic, hormonal, and clinical characteristics of equine endocrinopathic laminitis.. J Vet Intern Med 2019 May;33(3):1456-1463.
- Hardin JA, Wong JK, Cheeseman CI, Gall DG. Effect of luminal epidermal growth factor on enterocyte glucose and proline transport.. Am J Physiol 1996 Sep;271(3 Pt 1):G509-15.
- de Laat MA, McGree JM, Sillence MN. Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation.. Am J Physiol Endocrinol Metab 2016 Jan 1;310(1):E61-72.
- Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: recent advances.. F1000Res 2016;5.
- Bergeron JJ, Di Guglielmo GM, Dahan S, Dominguez M, Posner BI. Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction.. Annu Rev Biochem 2016 Jun 2;85:573-97.
- Zunke F, Rose-John S. The shedding protease ADAM17: Physiology and pathophysiology.. Biochim Biophys Acta Mol Cell Res 2017 Nov;1864(11 Pt B):2059-2070.
- de Laat MA, Kyaw-Tanner MT, Nourian AR, McGowan CM, Sillence MN, Pollitt CC. The developmental and acute phases of insulin-induced laminitis involve minimal metalloproteinase activity.. Vet Immunol Immunopathol 2011 Apr 15;140(3-4):275-81.
- Coyne MJ, Cousin H, Loftus JP, Johnson PJ, Belknap JK, Gradil CM, Black SJ, Alfandari D. Cloning and expression of ADAM-related metalloproteases in equine laminitis.. Vet Immunol Immunopathol 2009 Jun 15;129(3-4):231-41.
- Wang L, Pawlak E, Johnson PJ, Belknap JK, Alfandari D, Black SJ. Effects of cleavage by a disintegrin and metalloproteinase with thrombospondin motifs-4 on gene expression and protein content of versican and aggrecan in the digital laminae of horses with starch gruel-induced laminitis.. Am J Vet Res 2012 Jul;73(7):1047-56.
- Durham AE, Frank N, McGowan CM, Menzies-Gow NJ, Roelfsema E, Vervuert I, Feige K, Fey K. ECEIM consensus statement on equine metabolic syndrome.. J Vet Intern Med 2019 Mar;33(2):335-349.
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