Combined effects of TNF-α, IL-1β, and HIF-1α on MMP-2 production in ACL fibroblasts under mechanical stretch: an in vitro study.

Abstract

The dynamics between inflammatory factors, mechanical stress, and healing factors, in an intra-articular joint, are very complex after injury. Injury to intra-articular tissue [anterior cruciate ligament (ACL), synovium] results in hypoxia, accumulation of various pro-inflammatory factors, cytokines, and metalloproteases. Although the presence of increased amounts of matrix-metalloproteinases (MMP) in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP-2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury, inflammation and hypoxia induced factor-1α (HIF-1α) on induction of MMP-2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF-α and IL-1β elevate the activity of MMP-2 in a dose- and time-dependent manner. In addition, mechanical stretch further enhances the MMP-2 protein levels with TNF-α, IL-1β, and their mixture. CoCl(2) -induced HIF-1α (100 and 500 µM) also increases the levels and activity of MMP-2. Mechanical stretch has a strong additional effect on MMP-2 production with HIF-1α. Our results conclude that mechanical injury, HIF-1α and inflammatory factors collectively induce increased MMP-2 production in ACL fibroblasts, which was inhibited by NF-κB pathway inhibitor (Bay-11-7082).

• Authors: Yequan Wang, Zhenyu Tang, Ruyue Xue, Gurinder K Singh, Kunning Shi, Yonggang Lv, Li Yang
• Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society (J Orthop Res) Vol. 29 Issue 7 Pg. 1008-14 (Jul 2011) ISSN: 1554-527X [Electronic] United States
• PMID: 21344498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Orthpaedic Research Society.

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-1beta
• NF-kappa B
• Nitriles
• Sulfones
• Tumor Necrosis Factor-alpha
• Cobalt
• MMP2 protein, human
• Matrix Metalloproteinase 2
• cobaltous chloride

Topics

• Adult
• Anterior Cruciate Ligament (cytology)
• Cells, Cultured
• Cobalt (pharmacology)
• Drug Synergism
• Fibroblasts (cytology, drug effects, physiology)
• Humans
• Hypoxia (physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (pharmacology)
• In Vitro Techniques
• Inflammation (physiopathology)
• Interleukin-1beta (pharmacology)
• Matrix Metalloproteinase 2 (metabolism)
• Middle Aged
• NF-kappa B (antagonists & inhibitors)
• Nitriles (pharmacology)
• Stress, Mechanical
• Sulfones (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Young Adult