Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction.
OBJECTIVE
It has long been proposed that stromelysin is one of the major degradative matrix metalloproteinases responsible for the loss of cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA). This hypothesis was tested by examining the arthritic paws of stromelysin 1 (SLN1)-deficient mice for loss of cartilage and for generation of neoepitopes that would be indicative of aggrecan cleavage.


METHODS
The SLN1 gene was inactivated in murine embryonic stem cells, and knockout mice deficient in SLN1 activity were bred onto the B10.RIII background. The incidence and severity of collagen-induced arthritis (CIA) were compared in wild-type and knockout mice. Paws from mice with CIA were examined for loss of cartilage and for proteoglycan staining, as well as for the generation of the neoepitope FVDIPEN341.


RESULTS
SLN1-deficient mice developed CIA, as did the wild-type N2 mice. Histologic analyses demonstrated no significant differences among the B10.RIII, wild-type, and knockout mice in loss of articular cartilage and proteoglycan staining. No decrease in the FVDIPEN341 epitope was observed in the SLN1-deficient mice.


CONCLUSIONS
Disruption of the SLN1 gene neither prevents nor reduces the cartilage destruction associated with CIA. Moreover, SLN1 depletion does not prevent the cleavage of the aggrecan Asn341-Phe342 bond.
Mudgett
J S
JS
Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Hutchinson
N I
NI
Chartrain
N A
NA
Forsyth
A J
AJ
McDonnell
J
J
Singer
I I
II
Bayne
E K
EK
Flanagan
J
J
Kawka
D
D
Shen
C F
CF
Stevens
K
K
Chen
H
H
Trumbauer
M
M
Visco
D M
DM
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D015152:Blotting, Northern; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology*; D003094:Collagen; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D013234:Stem Cells
D000939:Epitopes; D012333:RNA, Messenger; D003094:Collagen; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3