Large‐scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis

Abstract

Objective. Despite many research efforts in recent decades, the major pathogenetic mechanisms of osteoarthritis (OA), including gene alterations occurring during OA cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. The present study was therefore initiated in order to identify differentially expressed disease-related genes and potential therapeutic targets.Methods. This investigation consisted of a large gene expression profiling study performed based on 78 normal and disease samples, using a custom-made complementary DNA array covering >4,000 genes.Results. Many differentially expressed genes were identified, including the expected up-regulation of anabolic and catabolic matrix genes. In particular, the down-regulation of important oxidative defense genes, i.e., the genes for superoxide dismutases 2 and 3 and glutathione peroxidase 3, was prominent. This indicates that continuous oxidative stress to the cells and the matrix is one major underlying pathogenetic mechanism in OA. Also, genes that are involved in the phenotypic stability of cells, a feature that is greatly reduced in OA cartilage, appeared to be suppressed.Conclusion. Our findings provide a reference data set on gene alterations in OA cartilage and, importantly, indicate major mechanisms underlying central cell biologic alterations that occur during the OA disease process. These results identify molecular targets that can be further investigated in the search for therapeutic interventions.

Hsp90 mediates insulin‐like growth factor 1 and interleukin‐1β signaling in an age‐dependent manner in equine articular chondrocytes

“…The relationship of diminished levels of Hsp90 protein in chondrocyte metabolism during OA has not been determined, but in another study, Hsp90 mRNA was diminished in OA compared with normal cartilage samples (9). Taken together, these findings suggest that decreased Hsp90 levels might play a role in ageassociated alterations in chondrocyte responses to external cues such as oxidative stress, which is an increasingly apparent contributor to older age-onset OA (38)(39)(40)(41)(42)(43)(44). Decreased levels of Hsp90 during aging may also contribute to altered growth factor responses and increased cellular senescence and therefore increased risk of older age-onset OA.…”

αvβ5 Integrin promotes dedifferentiation of monolayer-cultured articular chondrocytes

“…In these chondrocytes, the expression levels of type IX and type XI procollagens as well as link protein were higher than those in the cells given a control siRNA ( Figure 3C). In dedifferentiating chondrocytes, the expression levels of type I and type III procollagens, which are not very high in normal chondrocytes, have been shown to be induced in parallel with the decline in cartilage matrix gene expression (34)(35)(36)(37)(38). Thus, we expected that the expression of those procollagen genes might be reduced by the suppression of ␣v or ␤5 integrin expression.…”

Modulation of inflammation and oxidative stress in canine chondrocytes

“…During inflammation and/or oxidative stress, oxidative defense genes (i.e. SOD) are reported to be down-regulated in multiple tissues including astrocytes and chondrocytes (6,16,17). SOD has been discovered in three isoforms in humans.…”

“…Its main function is to protect cells and the ECM against the effects of superoxide anion (18). SOD2 has been shown to be down-regulated in OA while SOD3 is decreased in human OA and a mouse model of OA (16,22,23). Recently Scott et al found that all three SOD family members (SOD1, SOD2, and SOD3) were down regulated in diseased cartilage.…”

“…Regardless of the cause, chondrocyte damage results in a vicious cycle of extracellular matrix destruction; which is the hallmark of OA. This degradation of the cartilage matrix results from an imbalance between chondrocyte catabolic and anabolic events (14,15,16).…”