title: Targeting the T-cell membrane type-1 matrix metalloproteinase-CD44 axis in a transferred type 1 diabetes model in NOD mice.
abstract: This study tested the hypothesis that membrane-tethered type-1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific and K(d)-restricted IS-CD8(+) cells. To confirm the importance of MT1-MMP proteolysis of CD44 in type 1 diabetes (T1D), the anti-diabetic effects of three MMP inhibitors (3(S)-2,2-dimethyl-4[4-pyridin-4-yloxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamate [AG3340], 2-(4-phenoxyphenylsulfonylmethyl) thiirane [SB-3CT] and epigallocatechin-3-gallate [EGCG]) were compared using an adoptive diabetes transfer model in non-obese diabetic (NOD) mice. Only AG3340 was capable of inhibiting both the activity of MT1-MMP and the shedding of CD44 in T cells; and the transendothelial migration and homing of IS-CD8(+) T cells into the pancreatic islets. SB-3CT and EGCG were incapable of inhibiting T cell MT1-MMP efficiently. As a result, AG3340 alone, but not SB-3CT or EGCG, delayed the onset of transferred diabetes in NOD mice. In summary, the results of the present study emphasize that the MT1-MMP-CD44 axis has a unique involvement in T1D development. Accordingly, we suggest that a potent small-molecule MT1-MMP antagonist is required for the design of novel therapies for T1D.
authors: Sanford Research, University of South Dakota, Sioux Falls, SD 57105;
authors: Alexei Y
authors: AY
authors: Savinov
authors: Alex Y
authors: AY
authors: Strongin
keywords: CD44; T cell homing; metalloproteinases; migration; proteolysis; type 1 diabetes
references: Science. 2006 Mar 24;311(5768):1774-5
references: 16556844
references: J Biol Chem. 2005 Oct 7;280(40):33992-4002
references: 16046398
references: FASEB J. 2006 Sep;20(11):1793-801
references: 16940151
references: J Biol Chem. 1995 Mar 10;270(10):5331-8
references: 7890645
references: Expert Opin Emerg Drugs. 2003 May;8(1):179-92
references: 14610920
references: Immunity. 2004 Apr;20(4):455-65
references: 15084274
references: Nature. 2001 Dec 13;414(6865):792-8
references: 11742411
references: J Cell Biol. 2001 May 28;153(5):893-904
references: 11381077
references: J Exp Med. 2003 Mar 3;197(5):643-56
references: 12615905
references: J Biol Chem. 2003 Jul 18;278(29):27009-15
references: 12679334
references: Cancer Lett. 2004 Jul 8;210(1):47-55
references: 15172120
references: J Biol Chem. 2005 Jul 29;280(30):27755-8
references: 15944163
references: Arch Biochem Biophys. 2003 Jul 1;415(1):126-32
references: 12801521
references: J Biol Chem. 1993 Jul 5;268(19):14033-9
references: 8314771
references: J Med Chem. 2000 Jan 27;43(2):156-66
references: 10649971
references: Cancer Metastasis Rev. 2006 Mar;25(1):87-98
references: 16680575
references: Biochim Biophys Acta. 2002 Jan 30;1542(1-3):209-20
references: 11853893
references: Vitam Horm. 2009;80:541-62
references: 19251049
references: Nat Rev Cancer. 2002 Mar;2(3):161-74
references: 11990853
references: Circulation. 2001 May 8;103(18):2303-9
references: 11342481
references: Lab Invest. 2002 Dec;82(12):1685-93
references: 12480918
references: Biochim Biophys Acta. 2000 Mar 16;1478(1):51-60
references: 10719174
references: J Mol Med (Berl). 2003 Jan;81(1):4-19
references: 12545245
references: Oncogene. 2005 Jan 27;24(5):859-68
references: 15558018
references: Science. 2006 Mar 24;311(5768):1778-80
references: 16556846
references: J Exp Med. 1996 Jan 1;183(1):67-76
references: 8551245
references: J Biol Chem. 1991 Aug 25;266(24):15810-6
references: 1651920
references: Science. 2006 Mar 24;311(5768):1775-8
references: 16556845
references: Science. 1996 Apr 5;272(5258):60-6
references: 8600538
references: Cancer Lett. 2003 May 8;194(1):1-11
references: 12706853
references: Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1864-70
references: 16051878
references: Cancer Res. 2004 Dec 1;64(23):8657-65
references: 15574774
references: Diabetes. 2005 Sep;54(9):2612-9
references: 16123349