Abstract
Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H2O2-induced apoptosis in primary chondrocytes, suppressed H2O2- or IL-1ß−induced nitric oxide synthase (iNOS) production, and prevented IL-1ß−induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification.
Highlights
Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis
Effects of B3 on H2O2-induced Chondrocyte Apoptosis The protective effects of B3 against H2O2-mediated chondrocyte cell death were evaluated in epiphyseal primary chondrocytes
Chondrocyte apoptosis has been implicated in the pathogenesis of degenerative joint diseases, including osteoarthritis and rheumatoid arthritis [1,2,10]
Summary
Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. In OA, articular chondrocytes appear to be eliminated by apoptosis [1,2,3]. In response to cytokine stimulation, articular chondrocytes can produce a variety of reactive oxygen species (ROS), including peroxynitrite, superoxide anions, nitric oxide (NO), and hydrogen peroxide (H2O2) [4,5,6]. IL-1b induces chondrocyte death only when used in combination with oxygen radical scavengers or with a CD95 agonist [7,8]. Primary OA chondrocytes show both spontaneous and inducible levels of lipid peroxidation activity [9]. ROS are among the key inflammatory mediators involved in chondrocyte apoptosis observed in OA. H2O2 induces apoptosis in many cell types and may mediate cartilage degeneration associated with inflammatory joint diseases that induce chondrocyte apoptosis [10,11]
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