Insulin-like growth factor 1 blocks collagen release and down regulates matrix metalloproteinase-1, -3, -8, and -13 mRNA expression in bovine nasal cartilage stimulated with oncostatin M in combination with interleukin 1á

Objective—To investigate the eVect of insulin-like growth factor 1 (IGF1) on the release of collagen, and the production and expression of matrix metalloproteinases (MMPs) induced by the proinflammatory cytokine interleukin 1á (IL1á) in combination with oncostatin M (OSM) from bovine nasal cartilage and primary human articular chondrocytes. Methods—Human articular chondrocytes and bovine nasal cartilage were cultured with and without IGF1 in the presence of IL1á or IL1á + OSM. The release of collagen was measured by an assay for hydroxyproline. Collagenase activity was determined with the diVuse fibril assay using H acetylated collagen. The expression of MMP-1, MMP-3, MMP-8, MMP-13, and tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was analysed by northern blot. Results—IGF1 can partially inhibit the release of collagen induced by IL1á or IL1á + OSM from bovine nasal cartilage. This was accompanied by a reduced secretion and activation of collagenase by bovine nasal cartilage. IGF1 can also down regulate IL1á or IL1á + OSM induced MMP-1, MMP-3, MMP-8, and MMP-13 mRNA expression in human articular chondrocytes and bovine chondrocytes. It had no significant eVect on the production and expression of TIMP-1 mRNA in chondrocytes. Conclusion—This study shows for the first time that IGF1 can partially block the release of collagen from cartilage and suggests that down regulation of collagenases by IGF1 may be an important mechanism in preventing cartilage resorption initiated by proinflammatory cytokines. (Ann Rheum Dis 2001;60:254–261) Cartilage is a highly organised extracellular matrix in which proteoglycan (PG) and collagen fibrils are the two major structural components. PGs are complex, highly charged macromolecules with a high turnover rate, which pull water into the tissue and allow it to resist compression. The intact collagen network provides a permanent framework that gives tensile strength, and allows PG to be held in the matrix. Collagen has a low turnover rate, and when degradation of collagen does occur the structural integrity of the tissue is irreversibly lost. 2 The degradation of PG and collagen is a prominent feature of the cartilage loss seen in both rheumatoid arthritis (RA) and osteoarthritis (OA), and ultimately leads to joint destruction. Chondrocytes within cartilage play an important part in maintaining the surrounding matrix by modulating the synthesis and degradation of the various components in both normal and pathological conditions. During degenerative joint diseases, such as RA and OA, chondrocytes elicit a catabolic response which exceeds anabolism of new matrix molecules. The expression and production of proteolytic enzymes is increased and a major role is indicated for matrix metalloproteinases (MMPs), which can degrade matrix components. 4 Current knowledge points to the involvement of MMPs in the pathological destruction of cartilage in arthritis. Collagens can be specifically cleaved by the collagenases. Three mammalian collagenases (MMP-1, MMP-8, and MMP-13) can directly cleave the GlyLeu bond on the á1(II) chain, generating characteristic three quarter and one quarter length fragments. 6 After this cleavage the collagen fragments become susceptible to further degradation by other enzymes, such as stromelysin-1 (MMP-3) and gelatinases A and B (MMP-2 and MMP-9). MMP-3 is another potent enzyme in the turnover of cartilage components, in that it can cleave the N-telopeptide of type II collagen, which may lead to depolymerisation of type II collagen. 8 MMP-3 is also an activator of other MMPs, such as MMP-1 and MMP-9. 10 All these enzymes are expressed by chondrocytes. 11 These potent enzymes are controlled at key points that include the stimulation of synthesis and secretion by cytokines and growth factors, such as interleukin 1 (IL1) and tumour necrosis factor á, and the activation of proenzyme forms. 12 Tissue inhibitors of metalloproteinases (TIMPs), which are also expressed by chondrocytes, suppress the biological activity of collagenases. 14 Insulin-like growth factor (IGF) is a polypeptide with structural and functional homology to proinsulin. Human IGF1 and Ann Rheum Dis 2001;60:254–261 254 Department of Rheumatology, Medical School, University of Newcastle, Newcastle Upon Tyne, NE2 4HH, UK W Hui A D Rowan T Cawston