Open AccessCleavage of aggrecan at the Asn 341 –Phe 342 site coincides with the initiation of collagen damage in murine antigen‐induced arthritis: A pivotal role for stromelysin 1 in matrix metalloproteinase activity
Author(s) -
Van Meurs Joyce,
Van Lent Peter,
Stoop Reinout,
Holthuysen Astrid,
Singer Irwin,
Bayne Ellen,
Mudgett John,
Poole Robin,
Billinghurst Clark,
Van Der Kraan Peter,
Buma Pieter,
Van Den Berg Wim
Publication year - 1999
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/1529-0131(199910)42:10<2074::aid-anr7>3.0.co;2-5
Subject(s) - aggrecan , matrix metalloproteinase , cleavage (geology) , metalloproteinase , matrix metalloproteinase 3 , arthritis , chemistry , antigen , type ii collagen , immunology , medicine , microbiology and biotechnology , pathology , biology , biochemistry , osteoarthritis , articular cartilage , paleontology , fracture (geology) , alternative medicine
Objective The destruction of articular cartilage during arthritis is due to proteolytic cleavage of the extracellular matrix components. This study investigates the kinetic involvement of metalloproteinases (MMPs) in the degradation of the 2 major cartilage components, aggrecan and type II collagen, during murine antigen‐induced arthritis (AIA). In addition, the role of stromelysin 1 (SLN‐1) induction of MMP‐induced neoepitopes was studied. Methods VDIPEN neoepitopes in aggrecan and collagenase‐induced COL2‐3/4C neoepitopes in type II collagen were identified by immunolocalization. Stromelysin 1–deficient knockout (SLN1‐KO) mice were used to study SLN‐1 involvement. Results In AIA, the VDIPEN epitopes in aggrecan appeared after initial proteoglycan (PG) depletion. The collagenase‐induced type II collagen neoepitopes colocalized with VDIPEN epitopes. Remarkably, cartilage from arthritic SLN1‐KO mice showed neither the induction of VDIPEN nor collagen cleavage‐site neoepitopes during AIA, suggesting that stromelysin is a pivotal mediator in this process. PG depletion, as measured by the loss of Safranin O staining, was similar in SLN1‐KO mice and wild‐type strains. Furthermore, in vitro induction of VDIPEN epitopes in aggrecan and COL2‐3/4C epitopes in type II collagen, on exposure of cartilage to interleukin‐1, could not be accomplished in SLN1‐KO mice, whereas intense staining was achieved for both epitopes in cartilage of wild‐type strains. Conclusion This study emphasizes that SLN‐1 is essential in the induction of MMP‐specific aggrecan and collagen cleavage sites during AIA. It suggests that SLN‐1 is not a dominant enzyme in PG breakdown, but that it activates procollagenases and is crucial in the initiation of collagen damage.