Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Abstract

Objective-Oxidative stress is proposed as an important factor in osteoarthritis (OA). We therefore investigated the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA.Methods-SOD expression was determined by real-time polymerase chain reaction and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulfite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX™ and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression.Results-All three SOD were abundantly expressed in human cartilage but were markedly down-regulated in end-stage OA cartilage, especially SOD2. In the Dunkin Hartley guinea pig spontaneous OA model SOD2 expression was decreased in the medial tibial chondyle cartilage prior to, and following, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes gave an increase in ROS but a decrease in collagenase expression.Conclusion-This is the first comprehensive expression profile of all SOD genes in cartilage and importantly, using an animal model, we show that a reduction in SOD2 is associated with the earliest stages of OA. We found that a decrease in SOD2 associates with an increase in ROS and but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.

Modulation of inflammation and oxidative stress in canine chondrocytes

“…The present study showed that SOD levels can be induced using three different OA in human cartilage (14).…”

“…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).…”

“…Inflammatory cells release a variety of inflammatory mediators such as prostaglandins, leukotrienes, metalloproteinases (14), proteases, free radicals, interleukins (17), tumor necrosis factor (17), and other cytokines. Of particular interest are the roles of interleukin-6, interleukin-8, and IL-1β.…”

“…A major barrier in managing OA is the fact that it is not a single disease, but rather a disease with different pathophysiological mechanisms that results in damage to type II collagen (14). …”

Proteome Analysis During Chondrocyte Differentiation in a New Chondrogenesis Model Using Human Umbilical Cord Stroma Mesenchymal Stem Cells

“…Modulated proteins found to be up-regulated were procollagen-lysine (PLOD2), which stabilizes the synthesis of collagen type I and II and is involved in the chondrocytic response to TNF-␣-mediated stimuli affecting cartilage homeostasis (16), enolase (ENO1), which increases hypoxia tolerance and is involved in glycolysis (17), Heat shock protein beta-1 (HSPB1), which increases cell survival in changing environ- ments (18), superoxide dismutase (SODm), which destroys free radicals (a reduction in SODm is associated with the earliest stages of osteoarthritis in an animal model) (19), and zyxin (ZYX), which is involved in signaling pathways. Recent research elaborated by our group revealed that overexpression of Lamin A leads to defects in differentiation potential of MSCs.…”