Introduction: Myasthenia gravis (MG) is an autoimmune disease with weakness in striated musculature due to anti-acetylcholine receptor (AChR) antibodies or muscle specific kinase at the neuromuscular junction. A subgroup of patients has periocular symptoms only; ocular MG (OMG). Matrix metalloproteinases (MMP) are increased in several autoimmune diseases, including generalized MG (GMG), and have been suggested to play a role in immune cell infiltration, basement membrane breakdown and autoimmune pathogenesis. Methods: Total levels of MMP2, MMP3 and MMP9 were measured in serum by ELISA. Results: The MG patients had increased serum levels of MMP2 (median values 200.7 vs. 159.7 ng/ml, p < 0.001) and MMP9 (median values 629.6 vs. 386.4 ng/ml, p < 0.001) compared to controls. A subgroup of patients had increased MMP3 concentration (p = 0.001). The differences were not dependent on presence of AChR antibodies. No difference was observed between GMG and OMG patients with regard to MMP2 (p = 0.598), MMP3 (p = 0.450) and MMP9 (p = 0.271). Discussion: The increased MMP levels in our MG patients group and the lack of dependence on anti-AChR antibodies suggest that MMP2, MMP3 and MMP9 play a role in the development of MG. The similarities between GMG and OMG support OMG as a systemic disease.

1.
Conti-Fine BM, Milani M, Kaminski HJ: Myasthenia gravis: past, present, and future. J Clin Invest 2006;116:2843–2854.
2.
Romi F, et al: Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol 2005;62:442–446.
3.
Gilbert ME, Savino PJ: Ocular myasthenia gravis. Int Ophthalmol Clin 2007;47:93–103, ix.
4.
Evoli A, et al: Therapeutic options in ocular myasthenia gravis. Neuromuscul Disord 2001;11:208–216.
5.
Luchanok U, Kaminski HJ: Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008;21:8–15.
6.
Juel VC, Massey JM: Myasthenia gravis. Orphanet J Rare Dis 2007;2:44.
7.
Morrison CJ, et al: Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr Opin Cell Biol 2009;21:645–653.
8.
Murphy, G. and H. Nagase, Progress in matrix metalloproteinase research. Mol Aspects Med 2008;29:290–308.
9.
Romi FR, Gilhus NE, Luckman SP: Serum matrix metalloproteinase-3 levels are elevated in myasthenia gravis. J Neuroimmunol 2008;195:96–99.
10.
Kobayashi A, et al: Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med 2007;131:563–570.
11.
Kotajima L, et al: Increased levels of matrix metalloproteinase-3 in sera from patients with active lupus nephritis. Clin Exp Rheumatol 1998;16:409–415.
12.
Chen WS, et al: Autoantibody and biopsy grading are associated with expression of ICAM-1, MMP-3, and TRAIL in salivary gland mononuclear cells of Chinese patients with Sjogren’s syndrome. J Rheumatol 2009;36:989–996.
13.
Witzemann V: Development of the neuromuscular junction. Cell Tissue Res 2006;326:263–271.
14.
Matache C, et al: Matrix metalloproteinase-9 and its natural inhibitor TIMP-1 expressed or secreted by peripheral blood mononuclear cells from patients with systemic lupus erythematosus. J Autoimmun 2003;20:323–331.
15.
Kim WU, et al: Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res Ther 2005;7:R71–79.
16.
Gruber BL, et al: Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker. Clin Immunol Immunopathol 1996;78:161–171.
17.
Konttinen YT, et al: Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjögren’s syndrome. Matrix Biol 1998;17:335–347.
18.
Yong VW, et al: Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci 2007;259:79–84.
19.
Chakraborti S, et al: Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003;253:269–285.
20.
Ogata Y, Enghild JJ, Nagase H: Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem 1992;267:3581–3584.
21.
Vempati P, Karagiannis ED, Popel AS: A biochemical model of matrix metalloproteinase 9 activation and inhibition. J Biol Chem 2007;282:37585–37596.
22.
VanSaun M, et al: Activation of matrix metalloproteinase-3 is altered at the frog neuromuscular junction following changes in synaptic activity. Dev Neurobiol 2007;67:1488–1497.
23.
Chang YH, et al: Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Biochem 2008;41:955–959.
24.
Shiau MY, et al: Increased circulatory MMP-2 and MMP-9 levels and activities in patients with type 1 diabetes mellitus. Mt Sinai J Med 2006;73:1024–1028.
25.
Zhao XL, et al: MMP-mediated cleavage of beta-dystroglycan in myelin sheath is involved in autoimmune neuritis. Biochem Biophys Res Commun 2010;392:551–556.
26.
Brundula V, et al: Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297–1308.
27.
Hurnaus S, et al: Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors in inflammatory neuromuscular disorders. Eur Neurol 2006;55:204–208.
28.
Kherif S, et al: Expression of matrix metalloproteinases 2 and 9 in regenerating skeletal muscle: a study in experimentally injured and MDX muscles. Dev Biol 1999;205:158–170.
29.
Demestre M, et al: Characterization of matrix metalloproteinases in denervated muscle. Neuropathol Appl Neurobiol 2005;31:545–555.
30.
Zamecnik J, et al: Muscle lymphocytic infiltrates in thymoma-associated myasthenia gravis are phenotypically different from those in polymyositis. Neuromuscul Disord 2007;17:935–942.
31.
Kumagai K, et al: Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J Immunol 1999;162:4212–4219.
32.
Cai Y, Chen T, Xu Q: Astilbin suppresses delayed-type hypersensitivity by inhibiting lymphocyte migration. J Pharm Pharmacol 2003;55:691–696.
33.
Marracci GH, et al: Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol 2002;131:104–114.
34.
Werle MJ, VanSaun M: Activity dependent removal of agrin from synaptic basal lamina by matrix metalloproteinase 3. J Neurocytol 2003;32:905–913.
35.
Vincent A: Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2002;2:797–804.
36.
Drachman DB: Myasthenia gravis. N Engl J Med 1994;330:1797–1810.
37.
Leite MI, et al: IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008;131:1940–1952.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.