Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis

The Scripps Research Institute and the Scripps Clinic, La Jolla, California 92037, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 06/2006; 54(6):1814-21. DOI: 10.1002/art.21874
Source: PubMed


To examine the therapeutic efficacy of caspase inhibitors in experimental osteoarthritis (OA).
Experimental OA was induced in rabbits by anterior cruciate ligament transection (ACLT). Rabbits were treated with intraarticular (i.a.) injections of caspase inhibitors 3 times per week starting 1 week postoperatively. Animals were killed 9 weeks after ACLT, for macroscopic, histologic, and immunohistochemical assessment of the knee joints.
I.a. administration of the pan-caspase inhibitor Z-VAD-FMK significantly reduced cartilage degradation, as assessed by macroscopic and microscopic criteria. Untreated knees showed large numbers of chondrocytes with active caspase 3 and the p85 fragment of poly(ADP-ribose) polymerase (PARP p85) that is generated during apoptosis. The frequency of cells positive for PARP p85 and active caspase 3 was reduced in Z-VAD-FMK-treated knees. Inhibitors specific for caspase 3 or caspase 8 showed no significant efficacy. Caspase 1 inhibitor and the combination of caspase 3 and caspase 8 inhibitors reduced OA pathology.
These results provide direct support for a role of cell death in OA pathogenesis. Caspase inhibitors reduced the severity of cartilage lesions in experimental OA, suggesting that they may have disease-modifying activity in human OA.

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Available from: Martin Lotz, Sep 09, 2014
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    • "An increasing of chondrocyte apoptosis is considered a key pathological feature of OA and resent reports supported that OA chondrocytes appear mitochondrial dysfunction, which precedes the typical sign of apoptosis. Apoptosis of chondrocytes is a fundamental feature in OA cartilage degradation, and blockage of the pro-apoptotic pathway suppressed progression of OA (16). "
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    ABSTRACT: Withaferin A (WFA) is known as a constituent of Ayurvedic medicinal plant, Withania somnifera, and has been used for thousands of years. Although WFA has been used for the treatment of osteoarthritis (OA) and has a wide range of biochemical and pharmacologic activities, there are no findings suggesting its properties on chondrocytes or cartilage. The aim of the present study is to investigate the effects of WFA on apoptosis with focus on generation of intracellular reactive oxygen species (ROS). Here we showed that WFA significantly increased the generation of intracellular ROS in a dose-dependent manner. We also determined that WFA markedly leads to apoptosis as evidenced by accumulation of p53 by Western blot analysis. N-Acetyl-L-Cystein (NAC), an antioxidant, prevented WFA-caused expression of p53 and inhibited apoptosis of chondrocytes. We also found that WFA causes the activation of PI3K/Akt and JNKinase. Inhibition of PI3K/Akt and JNKinase with LY294002 (LY)/triciribine (TB) or SP600125 (SP) in WFA-treated cells reduced accumulation of p53 and inhibited fragmented DNA. Our findings suggested that apoptosis caused by WFA-induced intracellular ROS generation is regulated through PI3K/Akt and JNKinase in rabbit articular chondrocytes. Graphical Abstract
    Journal of Korean Medical Science 08/2014; 29(8):1042-53. DOI:10.3346/jkms.2014.29.8.1042 · 1.27 Impact Factor
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    • "In in vitro studies, chondrocyte apoptosis can be induced by exposing the normal cartilage explants or chondrocyte cultures either to biological [14,19,24] (e.g., nitric oxide (NO), collagenase, anti-CD95) or mechanical factors [10,11,25,26] (e.g., shear strain, loading strain). This effect can be inhibited by treatment with caspase inhibitor [24,27,28] (e.g., z.VAD.fmk), Insulin-like growth factor 1 (IGF-1) [24], N-acetylcysteine (NAC) [29] and p38 MAPK inhibitor [14]. "
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    ABSTRACT: Osteoarthritis (OA) is the most common joint disease characterised by degradation of articular cartilage and bone remodelling. For almost a decade chondrocyte apoptosis has been investigated as a possible mechanism of cartilage damage in OA, but its precise role in initiation and/or progression of OA remains to the determined. The aim of this study is to determine the role of chondrocyte apoptosis in spontaneous animal models of OA. Right tibias from six male Dunkin Hartley (DH) and Bristol Strain 2 (BS2) guinea pigs were collected at 10, 16, 24 and 30 weeks of age. Fresh-frozen sections of tibial epiphysis were microscopically scored for OA, and immunostained with caspase-3 and TUNEL for apoptotic chondrocytes. The DH strain had more pronounced cartilage damage than BS2, especially at 30 weeks. At this time point, the apoptotic chondrocytes were largely confined to the deep zone of articular cartilage (AC) with a greater percentage in the medial side of DH than BS2 (DH: 5.7%, 95% CI: 4.2-7.2), BS2: 4.8%, 95% CI: 3.8-5.8), p > 0.05). DH had a significant progression of chondrocyte death between 24 to 30 weeks during which time significant changes were observed in AC fibrillation, proteoglycan depletion and overall microscopic OA score. A strong correlation (p ≤ 0.01) was found between chondrocyte apoptosis and AC fibrillation (r = 0.3), cellularity (r = 0.4) and overall microscopic OA scores (r = 0.4). Overall, the rate of progression in OA and apoptosis over the study period was greater in the DH (versus BS2) and the medial AC (versus lateral). Chondrocyte apoptosis was higher at the later stage of OA development when the cartilage matrix was hypocellular and highly fibrillated, suggesting that chondrocyte apoptosis is a late event in OA.
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    • "Zhang et al. recently demonstrated the efficacy of intra-articular injections of the antitumor necrosis factor antibody infliximab in a rabbit model where the ACL and medial menisci were transected [129]. Other compounds including caspase inhibitors [130], chitinous materials [131, 132], resveratrol [133], and bisphosphonates [134, 135] have also been studied. "
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