title: Haem oxygenase-1 induction reverses the actions of interleukin-1β on hypoxia-inducible transcription factors and human chondrocyte metabolism in hypoxia.
abstract: HO-1 (haem oxygenase-1) catalyses the degradation of haem and possesses anti-inflammatory and cytoprotective properties. The role of inflammatory mediators in the pathogenesis of OA (osteoarthritis) is becoming increasingly appreciated. In the present study, we investigated the effects of HO-1 induction in OA and healthy HACs (human articular chondrocytes) in response to inflammatory cytokine IL-1 β (interleukin-1β) under hypoxic conditions. Hypoxia was investigated as it is a more physiological condition of the avascular cartilage. Hypoxic signalling is mediated by HIFs (hypoxia-inducible factors), of which there are two main isoforms, HIF-1α and HIF-2α. Normal and OA chondrocytes were stimulated with IL-1β. This cytokine suppresses HO-1 expression and exerts both catabolic and anti-anabolic effects, while increasing HIF-1α and suppressing HIF-2α protein levels in OA chondrocytes in hypoxia. Induction of HO-1 by CoPP (cobalt protoporphyrin IX) reversed these IL-1β actions. The hypoxia-induced anabolic pathway involving HIF-2α, SOX9 [SRY (sex determining region Y)-box 9] and COL2A1 (collagen type II α1) was suppressed by IL-1β, but importantly, levels were restored by HO-1 induction, which down-regulated TNFα (tumour necrosis factor α), MMP (matrix metalloproteinase) activity and MMP-13 protein levels. Depletion of HO-1 using siRNA (small interfering RNA) abolished the CoPP effects, further demonstrating that these were due to HO-1. The results of the present study reveal the different mechanisms by which HO-1 exerts protective effects on chondrocytes in physiological levels of hypoxia.
authors: Department of Pharmacology, University of Valencia, Spain.
authors: Victoria
authors: V
authors: Clérigues
authors: Christopher L
authors: CL
authors: Murphy
authors: Maria Isabel
authors: MI
authors: Guillén
authors: Maria José
authors: MJ
authors: Alcaraz
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D019902:Chondrocytes / Q000201:enzymology*; D024043:Collagen Type II / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024043:Collagen Type II; D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D020782:Matrix Metalloproteinases; D055758:SOX9 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000099162:Endothelial PAS Domain-Containing Protein 1; C499177:COL2A1 protein, human; C497442:HIF1A protein, human; C508585:IL1B protein, human; C527932:SOX9 protein, human; C496541:HMOX1 protein, human