Heme oxygenase-1 induction reverses interleukin-1{beta} actions on hypoxia inducible transcription factors and human chondrocyte metabolism in hypoxia

Heme oxygenase-1 (HO-1) catalyses the degradation of heme and possesses anti-inflammatory and cytoprotective properties. The role of inflammatory mediators in the pathogenesis of osteoarthritis (OA) is becoming increasingly appreciated. Here we investigated the effects of HO-1 induction in OA and healthy human articular chondrocytes in response to inflammatory cytokine interleukin-1β (IL-1 β) under hypoxic conditions. Hypoxia was investigated as it is a more physiological condition of the avascular cartilage. Hypoxic signalling is mediated by hypoxia inducible transcription factors (HIFs), of which there are two main isoforms, HIF-1α and HIF-2α. Normal and OA chondrocytes were stimulated with interleukin-1β (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 cobalt protoporphyrin IX (CoPP) reversed these IL-1β actions. The hypoxia-induced anabolic pathway involving HIF-2α, SOX9 and COL2A1 was suppressed by IL-1β, but importantly, levels were restored by HO-1 induction which down-regulated tumor necrosis factor-α, matrix metalloproteinase (MMP) activity and MMP-13 protein levels. Depletion of HO-1 using small interfering RNA abolished the CoPP effects, further demonstrating that these were due to HO-1. The results of this study reve...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research