Matrix metalloproteinases-1, -13 and their tissue inhibitor-1 in endocrine ophthalmopathy

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Effective regeneration of damaged soft orbital tissues in Graves’ ophthalmopathy (GO) requires coordinated remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) play an important role in the synthesis and degradation homeostasis of extracellular matrix components in various physiological and pathological conditions. Their proteolytic activity is inhibited by tissue inhibitors of metalloproteinases (TIMP). The biochemical processes taking place in extraocular muscles and retrobulbar tissue fibrogenesis in GO are not fully understood. Aims — to assess some biochemical mechanisms of extraocular muscles and retrobulbar tissue fibrogenesis in GO patients. Material and methods. The study included 65 people (130 eyes) at the age of 43 (35–50) years. Three groups of subjects were formed: 32 patients with a moderate GO severity (clinical group), 18 patients with autoimmune thyroid pathology without GO (comparison group), and 15 healthy persons (control). The diagnosis was based on clinical, laboratory, and instrumental data. A comprehensive ophthalmologic examination and blood sampling for determination of MMP-1, -13, TIMP-1, sulfated glycosaminoglycans (sGAG) and antibodies to thyroid-stimulating hormone receptor (TSHRAbs) were conducted. The data were statistically processed using the program Statistica 10.0. Results. An elevated level of MMP-13, observed in all GO patients (p<0.05). For the active phase of GOP, the comparison with the control group showed a 3.5-fold increase in MMP-13 (p<0.001) and 1.17-fold rise in TIMP-1 (p>0.05). Pulse glucocorticoid therapy reduced MMP-13 by 48.6% (p<0.001), TIMP-1 by 2.7% (p<0.001), and TSHRAbs — by 93% (p<0.001) compared with active GO, but these indicators were higher than the reference limits of control (p>0.05). In inactive GO, despite increased MMP-13, TIMP-1 decreased to the reference values (p=0.533). There were no significant differences in MMP-1 in groups of subjects (p=0.865). Conclusions. We have found imbalance between MMP-13 and TIMP-1 production in different activity phases of GO. Active GO is characterized by an increase in serum MMP-13 and TIMP-1. Dysregulation of intercellular matrix remodeling, possibly, underlies the development of extraocular muscles and retrobulbar tissue fibrosis in GO.

Keywords:

Graves’ ophthalmopathy

pathogenesis

fibrosis

matrix metalloproteinases

tissue inhibitor of metalloproteinases

glycosaminoglycans

Authors:

Taskina E.S.

Chita State Medical Academy, Chita, Russia

Kharintseva S.V.

Chita State Medical Academy, Chita, Russia

List of references:

Dedov II, Melnichenko GA, Sviridenko NYu, et al. Federal clinical recommendations on diagnostics and treatment of endocrine ophthalmopathy associated with autoimmune thyroid pathology. Problems of Endocrinology. 2015;61(1):61-74. (In Russ.) https://doi.org/10.14341/probl201561161-74
Petunina NA, Trukhina LV, Martirosyan NS. Endocrine ophthalmopathy: state-of-the-art approaches. Problems of Endocrinology. 2012;58(6):24-32. (In Russ.) https://doi.org/10.14341/probl201258624-32
Taskina ES, Kharintseva SV, Kharintsev VV. Current insights into the pathogenesis of the extraocular muscles and retrobulbar tissue impairments in endocrine ophthalmopathy. Zabaykal’skiy Meditsinskiy Vestnik. 2017;(2):175-184. (In Russ.)
Dik WA, Virakul S, Van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of graves’ ophthalmopathy. Exp Eye Res. 2016;142:83-91. https://doi.org/10.1016/j.exer.2015.02.007
Kharintsev VV, Serebryakova OV, Serkin DM, et al. The role of some pro- and anti-inflammatory cytokines in the course of endocrine ophthalmopathy. Zabaykal’skiy Meditsinskiy Vestnik. 2016;2:33-40. (In Russ.)
Bahn RS. Current insights into the pathogenesis of graves’ ophthalmopathy. Horm Metab Res. 2015;47(10):773-778. https://doi.org/10.1055/s-0035-1555762
Apte SS, Parks WC. Metalloproteinases: a parade of functions in matrix biology and an outlook for the future. Matrix Biol. 2015;44-46:1-6. https://doi.org/10.1016/j.matbio.2015.04.005
Shadrina AS, Plieva YaZ, Kushlinsky DN, et al. Classification, regulation of activity, genetic polymorphism of matrix metalloproteinases in norm and in pathology. Almanac of Clinical Medicine. 2017;45(4):266-279. (In Russ.) https://doi.org/10.18786/2072-0505-2017-45-4-266-279
Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European thyroid association/European group on graves’ orbitopathy guidelines for the management of graves’ orbitopathy. Eur Thyroid J. 2016;5(1):9-26. https://doi.org/10.1159/000443828
Krieger CC, Gershengorn MC. A modified ELISA accurately feasures secretion of high molecular weight hyaluronan (HA) by graves’ disease orbital cells. Endocrinology. 2014;155(2):627-634. https://doi.org/10.1210/en.2013-1890
Krieger CC, Neumann S, Place Rf, et al. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by graves’ disease immunoglobins. J Clin Endocrinol Metab. 2015;100(3):1071-1077. https://doi.org/10.1210/jc.2014-3566
Sufiyarov IF, Khasanov AG, Nurtdinov MA, et al. High level of glycosaminoglycans of blood serumas an independent predictor of the developing peritoneum adhesive disease. Creative Surgery and Oncology. 2017;7(2):48-53. (In Russ.) https://doi.org/10.24060/2076-3093-2017-7-2-48-53
Rogova LN, Shesternina NV, Zamechnik TV, Fastova IA. Matrix metalloproteinases, their role in physiological and pathological processes (review). Bulletin of New Medical Technologies. 2011;18(2):86-89. (In Russ.)
Govorin AV, Ratsina EV, Sokolova NA. Changes in matrix metalloproteinases and their tissue inhibitors in different forms of ischemic heart disease. Siberian Medical Journal. 2014;124(1):27-32. (In Russ.)
Arpino V, Brock M, Gill SE. The role of timps in regulation of extracellular matrix proteolysis. Matrix Biol. 2015;44-46:247-254. https://doi.org/10.1016/j.matbio.2015.03.005
Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPS): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803(1):55-71. https://doi.org/10.1016/j.bbamcr.2010.01.003
Myśliwiec J, Adamczyk M, Pawłowski P, et al. Serum gelatinases (MMP-2 and MMP-9) and VCAM-1 as a guideline in a therapeutic approach in Graves' ophthalmopathy. Endokrynol Pol. 2007;58(2):105-109.
Kim H, Choi YH, Park SJ, et al. Antifibrotic effect of pirfenidone on orbital fibroblasts of patients with thyroid-associated ophthalmopathy by decreasing TIMP-1 and collagen levels. Invest Ophthalmol Vis Sci. 2010;51(6):3061-3066. https://doi.org/10.1167/iovs.09-4257
Lei H, Leong D, Smith LR, Barton ER. Matrix metalloproteinase-13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration. Am J Physiol Cell Physiol. 2013;305(5):C529-C538. https://doi.org/10.1152/ajpcell.00051.2013
Wang W, Pan H, Murray K, et al. Matrix metalloproteinase-1 promotes muscle cell migration and differentiation. Am J Pathol. 2009;174(2):541-549. https://doi.org/10.2353/ajpath.2009.080509

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