Haem oxygenase‐1 regulates catabolic and anabolic processes in osteoarthritic chondrocytes

Abstract

Pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and other catabolic factors participate in the pathogenesis of cartilage damage in osteoarthritis (OA). Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) mediate cartilage degradation and might be involved in the progression of OA. Previously, we found that haem oxygenase-1 (HO-1) is down-regulated by pro-inflammatory cytokines and up-regulated by IL-10 in OA chondrocytes. The aim of this study was to determine whether HO-1 can modify the catabolic effects of IL-1beta in OA cartilage and chondrocytes. Up-regulation of HO-1 by cobalt protoporphyrin IX significantly reduced glycosaminoglycan degradation elicited by IL-1beta in OA cartilage explants but increased glycosaminoglycan synthesis and the expression of collagen II in OA chondrocytes in primary culture, as determined by radiometric procedures, immunoblotting and immunocytochemistry. HO-1 decreased the activation of extracellular signal-regulated kinase 1/2. This was accompanied by a significant inhibition in MMP activity and expression of collagenases MMP-1 and MMP-13 at the protein and mRNA levels. In addition, HO-1 induction caused a significant increase in the production of insulin-like growth factor-1 and a reduction in the levels of insulin-like growth factor binding protein-3. We have shown in primary culture of chondrocytes and articular explants from OA patients that HO-1 counteracts the catabolic and anti-anabolic effects of IL-1beta. Our data thus suggest that HO-1 may be a factor regulating the degradation and synthesis of extracellular matrix components in OA.

Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes

“…Although the reduction in heme availability may result in COX-2 protein possessing a low activity, our recent data [41] suggest that a product of HO-1 activity such as CO may be responsible for the reductions in PGE 2 production after HO-1 induction. Our results Recently, we have reported that HO-1 protects against cartilage degradation through the inhibition of the expression of several matrix metalloproteinases [20]. Here, we show for the first time a regulatory role of HO-1 in PGE 2 production due to mPGES-1 modulation, in primary OA chondrocytes stimulated with IL-1, which may participate in the observed protective effects on cartilage.…”

“…Our data suggest that the inhibitory effects of HO-1 induction on the first transcription factor could play a role in the recently reported inhibition of MMP expresion [20]. Although the COX-2 promoter contains multiple regulatory sites including those able to interact with both transcription factors, it has been reported that COX-2 induction by IL-1 in human chondrocytes may be dependent on other transcription factors [44], which would be consistent with the lack of effect of CoPP on COX-2 expression.…”

“…PCR assays were performed in duplicate on an iCycler Real-Time PCR Detection System using SYBR Green PCR Master Mix (Bio-Rad Laboratories, Richmond, CA, USA) as previously described [20]. Primer sequences are shown in table 1.…”

“…According to previous studies [20], we used CoPP (10 M) to induce HO-1 in OA chondrocytes. To determine whether cell viability is modified in our experimental conditions, we performed LSC experiments.…”

“…Recently, we have also shown a protective effect of HO-1 induction on cartilage degradation [20]. We hypothesized that HO-1 could control metabolic processes in chondrocytes relevant in the progression of OA.…”