Gelatinase expression and proteolytic activity in giant-cell arteritis.
OBJECTIVE
Gelatinases (MMP2 and MMP9) are expressed in giant-cell arteritis (GCA) and are thought to play a role in vessel disruption. However, their activation status and enzymatic activity have not been evaluated. Our aim was to investigate the distribution and proteolytic activity of gelatinases in GCA lesions at different stages.


METHODS
Expression of MMP2, MMP9, MMP2-activator MMP14 and their natural inhibitors TIMP1 and TIMP2 was determined by real-time PCR and immunohistochemistry in temporal artery sections from 46 patients and 12 controls. MMP activation status and enzymatic activity were assessed by gelatin and film in situ zymography.


RESULTS
Vascular smooth muscle cells from normal specimens constitutively expressed pro-MMP2 and its inhibitor TIMP2 with no resulting proteolytic activity. In GCA MMP2, MMP9 and MMP14 were strongly expressed in their active form by infiltrating leucocytes. Inflamed arteries also expressed TIMP1 and TIMP2. However, the MMP9/TIMP1 and MMP2/TIMP2 ratios were higher in patients compared with controls, indicating an increased proteolytic balance in GCA which was confirmed by in situ zymography. Maximal gelatinase expression and activity occurred at the granulomatous areas surrounding the internal elastic lamina (IEL). Myointimal cells also expressed MMPs and exhibited proteolytic activity, suggesting a role for gelatinases in vascular remodelling and repair.


CONCLUSIONS
GCA lesions show intense expression of gelatinases. Activators and inhibitors are regulated to yield enhanced gelatinase activation and proteolytic activity. Distribution of expression and proteolytic activity suggests that gelatinases have a major role not only in the progression of inflammatory infiltrates and vessel destruction but also in vessel repair.
Segarra
Marta
M
Vasculitis Research Unit, Department of Internal Medicine, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain.
García-Martínez
Ana
A
Sánchez
Montse
M
Hernández-Rodríguez
José
J
Lozano
Ester
E
Grau
Josep M
JM
Cid
Maria C
MC
D001706:Biopsy; D004789:Enzyme Activation; D018093:Gelatinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D013700:Giant Cell Arteritis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013699:Temporal Arteries / Q000201:enzymology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D005938:Glucocorticoids; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14