Abstract
We reported at the Keynote Forum of Immunology Summit-2015 that recombinant human (rh) TNF-α or rhIL-6 stimulated production of matrix metalloproteinase-9 (MMP-9) in the T/C28a2 and C-28/I2 human immortalized chondrocyte cell lines. Furthermore, we reported that tocilizumab (TCZ), a fully humanized monoclonal antibody which neutralizes IL-6-mediated signaling, inhibited the rhIL-6-mediated increase in the production of MMP-9. IL-6 is also a known activator of the JAK/STAT signaling pathway. In that regard, we evaluated the effect of rhIL-6 on total and phosphorylated Signal Transducer and Activator of Transcription by these chondrocyte lines which showed that whereas STAT3 was constitutively phosphorylated in T/C28a2 chondrocytes, rhIL-6 activated STAT3 in C-28/I2 chondrocytes. The finding that rhIL-6 increased the production of MMP-9 by human immortalized chondrocyte cell lines may have important implications with respect to the destruction of articular cartilage in rheumatoid arthritis and osteoarthritis. Thus, the markedly elevated level of IL-6 in rheumatoid arthritis and osteoarthritis sera and synovial fluid would be expected to generate significant MMP-9 to cause the degradation of articular cartilage extracellular matrix proteins. The finding that TCZ suppressed rhIL-6-mediated MMP-9 production suggests that TCZ, currently employed in the medical therapy of rheumatoid arthritis, could be considered as a drug for osteoarthritis.
Highlights
It is acknowledged that the pathologic mechanisms that contribute to rheumatoid arthritis (RA) and osteoarthritis (OA) are significantly different, there are overlapping pathophysiological components which are characteristic of each disease process [1]
We reported at Immunology Summit-2015 that matrix metalloproteinase-9 (MMP-9) production was significantly increased by rhIL-6 (50ng/ml) or by recombinant human TNF-α (rhTNF-α) (20ng/ml) in both T/C28a2 and C-28/I2 chondrocyte cell lines as well as by PANC-1 cells treated with phorbol myristate acetate
To summarize the results of these in vitro studies presented at Immunology Summit-2015 we showed that TCZ, a monoclonal antibody that neutralizes the activity of IL-6 mainly via IL-6/IL-6Rα/gp130 signaling, inhibited rhIL-6-stimulated MMP-9 production in the immortalized human chondrocyte cell lines, T/C28a2 and C-28/I2, whereas the combination of rhTNF-α and TCZ did not inhibit MMP-9 production [14]
Summary
It is acknowledged that the pathologic mechanisms that contribute to rheumatoid arthritis (RA) and osteoarthritis (OA) are significantly different, there are overlapping pathophysiological components which are characteristic of each disease process [1]. Most prominent of these overlapping characteristics of OA and RA is the significant increase in the serum and synovial fluid levels of pro-inflammatory cytokines, exemplified by tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 [2,3]. MMP-9 is a potent enzyme mediator of cartilage destruction based on the accumulation of evidence which showed that MMP-9 could efficiently degrade many of the articular cartilage ECM proteins that are critical for maintaining the structural integrity of this musculoskeletal tissue [7,8,9,10]
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