title: 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.affiliation: Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
authors.forename: Yequan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Tang
authors.forename: Ruyue
authors.initials: R
authors.lastname: Xue
authors.forename: Gurinder K
authors.initials: GK
authors.lastname: Singh
authors.forename: Kunning
authors.initials: K
authors.lastname: Shi
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Lv
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D000328:Adult; D016118:Anterior Cruciate Ligament / Q000166:cytology*; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000494:pharmacology*; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology; D053583:Interleukin-1beta / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D013314:Stress, Mechanical; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D003035:Cobalt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C018021:cobaltous chloride