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SAT0572 The Effect of Interleukin-4 on Mechanical Stress-Induced Protease Expressions by Human Chondrocytes
  1. T. Machida1,
  2. K. Nishida1,2,
  3. K. Hashizume1,
  4. R. Nakahara1,
  5. M. Ozawa1,
  6. R. Harada1,
  7. T. Ozaki1
  1. 1Department of Orthopaedic surgery
  2. 2Department of Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama city, Japan


Background We previously reported that runt-related transcription factor 2 (RUNX-2) has an important role in regulation of mechanical stress-induced expression of ADAMTS aggrecanases in chondrocytes. Interleukin-4 (IL-4) is an anti-inflammatory cytokine, like IL-10 and IL-13, which is known to suppress pro-inflammatory cytokine production and activities. In osteoarthritis (OA) synovial tissue, IL-4 inhibits the production of tumor necrosis factor-α and IL-1β. Local overexpression of IL-4 protects cartilage from metalloproteinase (MMP)-induced destruction by preventing the activation of pro-MMPs during immune complex-mediated arthritis. More recently, we reported that intra-articular injection of IL-4 ameliorates subsequent destruction of cartilage in instability-induced OA in rat knee joints.

Objectives To examine the effect of IL-4 on mechanical stress-induced expression of catabolic proteases by human chondrocytes.

Methods Normal Human Articular Chondrocytes from knee joint were purchased from Lonza (Walkersville, MD, USA). IL-4 was purchased from CHEMICON International, Inc. (Temecula, USA). Cells were cultured at 37°, and were seeded onto type II collagen coated stretch chambers. They were transferred to serum-free medium with or without IL-4 (10ng/ml) for 12h before cyclic tensile strain (CTS), and a uni-axial CTS (0.5 Hz, 10% elongation) was applied for 30 min using the ST-140 mechanical stretch system (STREX, Osaka, Japan). RNA was isolated at 1, 6, 12, 24h after CTS, reverse transcribed, and the expression of ADAMTS-4, -5, -9, MMP-13, and RUNX-2 examined by real-time PCR.

Results CTS induced the expression of ADAMTS-4, -9, MMP-13 at 24h, and MMP-3 at 6h after CTS in control samples. In IL-4 treated samples, the expression of ADAMTS-4, -5, -9, MMP-13 and RUNX-2 were significantly downregulated. ADAMTS-5 gene expression was biphasic (1h and 12h after CTS) in control samples, and both peaks (RUNX-2 dependent peak and cytokine dependent peak) were reduced in IL-4 treated samples. The concentration of IL-1β in the supernatant increased in control samples at 6h after CTS, but decreased in IL-4 treated samples.

Conclusions IL-4 treatment effectively suppressed the mechanical stress-induced expression of ADAMTS-4, -5, -9 and MMP-13, presumably by inhibition through RUNX-2 pathways. These data suggest the clinical chondro-protective effects of IL-4 against mechanical stress-induced cartilage degeneration.


  1. Tetsunaga T, Nishida K, Furumatsu T, Naruse K, Hirohata S, et al.Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells. Osteoarthritis Cartilage 2011; 19: 222-232.

  2. Goldring MB: The role of the chondrocyte in osteoarthritis. Arthritis Rheum 2000; 43: 1916-1926.

  3. Bendrups A, Hilton A, Meager A and Hamilton JA: Reduction of tumor necrosis factor alpha and interleukin-1 beta levels in human synovial tissue by interleukin-4 and glucocorticoid. Rheumatol Int 1993; 12: 217-220.

  4. Yorimitsu M, Nishida K, Shimizu A, et al: Intra-articular injection of interleukin-4 decreases nitric oxide production by chondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints. Osteoarthritis Cartilage 16(7): 764-71, 2008

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.4837

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