Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis.
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.
Mahmoodi
Mandana
M
Joint Diseases Laboratory, Shriners Hospital for Children, 1529 Cedar Ave., Montreal, Quebec, Canada H3G 1A6.
Sahebjam
Solmaz
S
Smookler
David
D
Khokha
Rama
R
Mort
John S
JS
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D053674:Aggrecans; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001168:Arthritis / Q000139:chemically induced / Q000473:pathology*; D004396:Coloring Agents; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007270:Injections, Intra-Articular; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010619:Phenazines; D011509:Proteoglycans / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
C508320:Acan protein, mouse; D053674:Aggrecans; D000941:Antigens; D004396:Coloring Agents; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D010619:Phenazines; D011509:Proteoglycans; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D012710:Serum Albumin, Bovine; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C009195:safranine T