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

• Published in: The American journal of pathology Vol. 166; no. 6; pp. 1733 - 1740
• Main Authors: Mahmoodi, Mandana, Sahebjam, Solmaz, Smookler, David, Khokha, Rama, Mort, John S.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.06.2005; ASIP; American Society for Investigative Pathology
• Subjects: ADAM Proteins; ADAM17 Protein; Aggrecans; Animals; Antigens - administration & dosage; Arthritis - chemically induced; Arthritis - pathology; Biological and medical sciences; Coloring Agents; Disease Models, Animal; Diseases of the osteoarticular system; Extracellular Matrix Proteins - metabolism; Immunohistochemistry; Inflammation - chemically induced; Inflammation - pathology; Inflammatory joint diseases; Injections, Intra-Articular; Investigative techniques, diagnostic techniques (general aspects); Lectins, C-Type; Medical sciences; Metalloendopeptidases - metabolism; Mice; Mice, Knockout; Original Research Paper; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenazines; Proteoglycans - metabolism; Serum Albumin, Bovine - administration & dosage; Tissue Inhibitor of Metalloproteinase-3 - deficiency; Tumor Necrosis Factor-alpha - analysis; Antigen; Tissue inhibitor metalloproteinase 3; Anatomic pathology; Inflammatory joint disease; Inflammatory arthritis; Diseases of the osteoarticular system
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)62483-2

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is known to inhibit matrix metalloproteinases, aggrecanases, and tumor necrosis factor (TNF)-α-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-α 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-α 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-α by reducing ADAM17 activity.