Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage.
OBJECTIVE
To determine whether interleukin-1 (IL-1) or tumor necrosis factor alpha (TNFalpha), or both, plays a role in the excessive degradation that is observed in cultured osteoarthritic (OA) articular cartilage.


METHODS
Antagonists of IL-1 and TNFalpha, namely, IL-1 receptor antagonist and the PEGylated soluble TNFalpha receptor I, respectively, were added at different concentrations to explant cultures of nonarthritic (5 obtained at autopsy) and OA (15 obtained at arthroplasty) articular cartilage. The cleavage of type II collagen (CII) by collagenase was measured by an immunoassay in cartilage and culture media. Proteoglycan (mainly aggrecan) content and degradation were measured by a colorimetric assay for glycosaminoglycan (GAG) content in cartilage and culture media. Reverse transcriptase-polymerase chain reaction was used to analyze gene expression of matrix metalloproteases (MMPs) 1, 3, and 13, CII, aggrecan, IL-1, and TNFalpha.


RESULTS
Antagonists of IL-1 and TNFalpha inhibited the increase in CII cleavage by collagenase as well as the increase in GAG release observed in OA cartilage compared with normal cartilage. Inhibition was significant in tissue from some patients but not from others, although significant inhibition was observed when all the results were analyzed together. An increase in the GAG content in cartilage was seen in 4 of 15 cases. However, this increase was not significant when all the data were combined. Preliminary results indicated no effect of these antagonists on nonarthritic cartilage from 3 different donors. Independent analyses of gene expression in cultured cartilage from 9 other OA patients revealed that IL-1 or TNFalpha blockade, either alone and/or in combination, frequently down-regulated MMP-1, MMP-3, and MMP-13 expression. Expression of IL-1 and TNFalpha was inhibited by either antagonist or by the combination in essentially half the cases. The combined blockade up-regulated aggrecan and CII gene expression in approximately half the cases.


CONCLUSIONS
These results suggest that the autocrine/paracrine activities of TNFalpha and IL-1 in articular cartilage may play important roles in cartilage matrix degradation in OA patients but not in all patients. Inhibition of either or both of these cytokines may offer a useful therapeutic approach to the management of OA by reducing gene expression of MMPs involved in cartilage matrix degradation and favoring its repair.
Kobayashi
Masahiko
M
Joint Diseases Laboratory, Departments of Surgery and Medicine, Shriners Hospital for Children, McGill University, 1529 Cedar Avenue, Montreal, Quebec H3G 1A6, Canada.
Squires
Ginette R
GR
Mousa
Aisha
A
Tanzer
Michael
M
Zukor
David J
DJ
Antoniou
John
J
Feige
Ulrich
U
Poole
A Robin
AR
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism*; D016022:Case-Control Studies; D024043:Collagen Type II / Q000737:chemistry / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018501:Antirheumatic Agents; D024043:Collagen Type II; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C496217:PEGylated tumor necrosis factor alpha receptor 1; D011509:Proteoglycans; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D017364:Collagenases