Lack of cathepsin activities alter or prevent the development of lung granulomas in a mouse model of sarcoidosis.
BACKGROUND
Remodeling of lung tissues during the process of granuloma formation requires significant restructuring of the extra-cellular matrix and cathepsins K, L and S are among the strongest extra-cellular matrix degrading enzymes. Cathepsin K is highly expressed in various pathological granulomatous infiltrates and all three enzymes in their active form are detected in bronchoalveolar lavage fluids from patients with sarcoidosis. Granulomatous inflammation is driven by T-cell response and cathepsins S and L are actively involved in the regulation of antigen presentation and T-cell selection. Here, we show that the disruption of the activities of cathepsins K, L, or S affects the development of lung granulomas in a mouse model of sarcoidosis.


METHODS
Apolipoprotein E-deficient mice lacking cathepsin K or L were fed Paigen diet for 16 weeks and lungs were analyzed and compared with their cathepsin-expressing littermates. The role of cathepsin S in the development of granulomas was evaluated using mice treated for 8 weeks with a potent and selective cathepsin S inhibitor.


RESULTS
When compared to wild-type litters, more cathepsin K-deficient mice had lung granulomas, but individually affected mice developed smaller granulomas that were present in lower numbers. The absence of cathepsin K increased the number of multinucleated giant cells and the collagen content in granulomas. Cathepsin L deficiency resulted in decreased size and number of lung granulomas. Apoe-/- mice treated with a selective cathepsin S inhibitor did not develop lung granulomas and only individual epithelioid cells were observed.


CONCLUSIONS
Cathepsin K deficiency affected mostly the occurrence and composition of lung granulomas, whereas cathepsin L deficiency significantly reduced their number and cathepsin S inhibition prevented the formation of granulomas.
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.
Andriy O
AO
Samokhin
Jacques Yves
JY
Gauthier
M David
MD
Percival
Dieter
D
Brömme
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D056657:Cathepsin K / Q000172:deficiency* / Q000235:genetics; D056668:Cathepsin L / Q000172:deficiency* / Q000235:genetics; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015769:Granuloma, Respiratory Tract / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006984:Hypertrophy; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology*; D017565:Sarcoidosis, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000201:enzymology / Q000473:pathology; D013997:Time Factors
D001057:Apolipoproteins E; D011480:Protease Inhibitors; D003094:Collagen; D002403:Cathepsins; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S; D056657:Cathepsin K; C534132:Ctsk protein, mouse
Biol Chem. 2006 Jul;387(7):863-70
16913835
Immunity. 1999 Feb;10(2):207-17
10072073
FASEB J. 2000 Oct;14(13):2075-86
11023992
Mol Med. 2000 Aug;6(8):648-59
11055584
J Clin Invest. 1998 Jun 1;101(11):2351-63
9616206
J Exp Med. 2007 Apr 16;204(4):723-34
17371929
Clin Dermatol. 2007 May-Jun;25(3):232-41
17560300
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4929-33
17590332
Immunol Rev. 2005 Oct;207:229-41
16181340
J Exp Med. 2002 May 20;195(10):1349-58
12021314
J Biol Chem. 1992 Apr 15;267(11):7258-62
1373132
Immunity. 1996 Apr;4(4):357-66
8612130
Semin Respir Crit Care Med. 2007 Feb;28(1):3-14
17330188
Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1166-73
20203298
Clin Chest Med. 2008 Sep;29(3):379-90, vii
18539233
J Immunol. 2005 Jun 1;174(11):7022-32
15905545
J Cell Sci. 2009 Feb 15;122(Pt 4):453-9
19155290
Eur Respir J. 2004 Apr;23(4):620-8
15083765
Clin Chest Med. 2008 Sep;29(3):565-74, x
18539245
Am J Respir Crit Care Med. 2007 Oct 15;176(8):778-85
17673697
Proc Am Thorac Soc. 2007 Aug 15;4(5):461-4
17684290
Am J Pathol. 2004 Jun;164(6):2203-16
15161653
Circulation. 2006 Jan 3;113(1):98-107
16365196
J Biol Chem. 1996 Jan 26;271(4):2126-32
8567669
Respir Res. 2000;1(3):170-7
11667982
Science. 1998 Apr 17;280(5362):450-3
9545226
Int J Biochem Cell Biol. 2008;40(6-7):1079-94
18093865
Semin Respir Crit Care Med. 2007 Feb;28(1):53-74
17330192
Nat Rev Immunol. 2003 Jun;3(6):472-82
12776207
Atherosclerosis. 2008 Sep;200(1):58-68
18291403
Child Neuropsychol. 2009 Nov;15(6):582-604
19492202
Biol Cell. 2006 Jan;98(1):15-22
16354158
J Pathol. 2006 Nov;210(3):334-43
16972305
Biol Chem. 1999 Jun;380(6):679-87
10430032
Pulm Pharmacol Ther. 2009 Feb;22(1):27-32
19041950
Clin Exp Immunol. 2009 Mar;155(3):476-86
19077083
Am J Pathol. 2010 Mar;176(3):1148-56
20093498
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13453-8
9811821
Clin Dermatol. 2007 May-Jun;25(3):250-8
17560302
J Pathol. 2001 Oct;195(3):375-82
11673837