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(American Journal of Pathology. 2005;166:1733-1740.)
© 2005 American Society for Investigative Pathology

Lack of Tissue Inhibitor of Metalloproteinases-3 Results in an Enhanced Inflammatory Response in Antigen-Induced Arthritis

Mandana Mahmoodi*, Solmaz Sahebjam*, David Smookler{dagger}, Rama Khokha{dagger} and John S. Mort*

From the Joint Diseases Laboratory, Shriners Hospital for Children, and Departments of Surgery and Medicine,* McGill University, Montreal, Quebec; and The Ontario Cancer Institute,{dagger} University of Toronto, Toronto, Ontario, Canada

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is known to inhibit matrix metalloproteinases, aggrecanases, and tumor necrosis factor (TNF)-{alpha}-converting enzyme (TACE, ADAM17). These metalloproteases participate in different aspects of joint destruction in inflammatory arthritis. To determine the relative importance of this inhibitor in joint pathology, wild-type and Timp3–/– mice were immunized with methylated bovine serum albumin followed by arthritis induction by intra-articular injection of the same antigen. Animals were monitored for up to 14 days after challenge, and joint tissues were analyzed by routine and Safranin O staining and for the presence of aggrecan neoepitopes produced by metalloprotease cleavage. Serum TNF-{alpha} was measured by immunoassay. Compared to wild-type animals, Timp3–/– mice showed a dramatic increase in the initial inflammatory response to intra-articular antigen injection, and serum TNF-{alpha} levels were greatly elevated in the Timp3–/– animals after immunization. However, these differences in clinical features disappeared by days 7 to 14. No difference in Safranin O staining or aggrecan cleavage site neoepitope abundance was seen. Thus, in inflammatory joint disease TIMP-3 likely dampens the inflammatory response of TNF-{alpha} by reducing ADAM17 activity.




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