Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis

D’Lima, Darryl D.; Hermida, Juan C.; Hashimoto, Sanshiro; Colwell, Clifford W.; Lotz, Martin

doi:10.1002/art.21874

Cited by 156 publications

(131 citation statements)

References 56 publications

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“…Apoptosis of chondrocytes is another pathologic feature of OA cartilage, the rate of which appears to correlate with disease severity (26). Studies have shown that contributing factors mediating the apoptosis of chondrocytes include mitochondrial dysfunction, decreased ATP levels, and the generation of reactive oxygen species (2).…”

Section: Resultsmentioning

confidence: 99%

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

Dave

Attur

Palmer

et al. 2008

Arthritis & Rheumatism

122

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Objective. To determine the effects of the antioxidant resveratrol on the functions of human chondrocytes in osteoarthritis (OA).Methods. Chondrocytes and cartilage explants were isolated from OA patients undergoing knee replacement surgery. Effects of resveratrol in the presence or absence of interleukin-1␤ (IL-1␤) stimulation were assessed by measurement of prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) synthesis, cyclooxygenase (COX) activity, matrix metalloproteinase (MMP) expression, and proteoglycan production. To explore the mechanisms of action of resveratrol, its effects on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, cytochrome c release, and annexin V staining.Results. Resveratrol inhibited both spontaneous and IL-1␤-induced PGE 2 production by >20% (P < 0.05) and by 80% (P < 0.001), respectively; similarly, LTB 4 production was reduced by >50% (P < 0.05). The production of PGE 2 was inhibited via a 70-90% suppression of COX-2 expression and enzyme activity (P < 0.05). Resveratrol also promoted anabolic effects in OA explant cultures, by elevating proteoglycan synthesis and decreasing production of MMPs 1, 3, and 13. Pretreatment of OA chondrocytes with resveratrol blocked mitochondrial membrane depolarization, loss of mitochondrial biomass, and IL-1␤-induced ATP depletion. Similarly, IL-1␤-mediated induction of the apoptotic markers cytochrome c and annexin V was also inhibited by resveratrol. Exogenous addition of PGE 2 abolished the protective effects of resveratrol on mitochondrial membrane integrity, ATP levels, expression of apoptotic markers, and DNA fragmentation.Conclusion. Resveratrol protects against IL-1␤-induced catabolic effects and prevents chondrocyte apoptosis via its inhibition of mitochondrial membrane depolarization and ATP depletion. These beneficial effects of resveratrol are due, in part, to its capacity to inhibit COX-2-derived PGE 2 synthesis. Resveratrol may therefore protect against oxidant injury and apoptosis, which are main features of progressive OA.

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Section: Resultsmentioning

confidence: 99%

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

Dave

Attur

Palmer

et al. 2008

Arthritis & Rheumatism

122

View full text Add to dashboard Cite

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“…Furthermore, shear strain is exaggerated in degenerative cartilage samples (32). Also of interest are reports that administering pancaspase inhibitors to experimental OA models resulted in fewer cartilage lesions by preventing cell death (8,36).…”

Section: Discussionmentioning

confidence: 99%

“…Ultimately, the combination of increased friction, loss of proteoglycan within the cartilage matrix, and chondrocyte death progresses to endstage OA, characterized by full-thickness cartilage loss (3)(4)(5). Support for this hypothesis derives from studies demonstrating the critical role of chondrocytes in maintaining the articular cartilage matrix (6,7) and associating chondrocyte apoptosis with OA pathology (8)(9)(10). However, a direct connection between friction and chondrocyte apoptosis has not yet been demonstrated in the context of lubricating SF components.…”

mentioning

confidence: 99%

Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis

Waller

Zhang

Elsaid

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

218

179

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Osteoarthritis is a complex disease involving the mechanical breakdown of articular cartilage in the presence of altered joint mechanics and chondrocyte death, but the connection between these factors is not well established. Lubricin, a mucinous glycoprotein encoded by the PRG4 gene, provides boundary lubrication in articular joints. Joint friction is elevated and accompanied by accelerated cartilage damage in humans and mice that have genetic deficiency of lubricin. Here, we investigated the relationship between coefficient of friction and chondrocyte death using ex vivo and in vitro measurements of friction and apoptosis. We observed increases in whole-joint friction and cellular apoptosis in lubricin knockout mice compared with wild-type mice. When we used an in vitro bovine explant cartilage-on-cartilage bearing system, we observed a direct correlation between coefficient of friction and chondrocyte apoptosis in the superficial layers of cartilage. In the bovine explant system, the addition of lubricin as a test lubricant significantly lowered the static coefficient of friction and number of apoptotic chondrocytes. These results demonstrate a direct connection between lubricin, boundary lubrication, and cell survival and suggest that supplementation of synovial fluid with lubricin may be an effective treatment to prevent cartilage deterioration in patients with genetic or acquired deficiency of lubricin.camptodactyly-arthropathy-coxa vara-pericarditis | shear strain | antiadhesion | tribology

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“…However, the effect of hyaluronan on prevention of OA seems to be limited according to several metaanalyses. 17 Recently, novel approaches such as injection of caspase inhibitors, 18 treatment with basic fibroblast growth factor, 19 oral doxycycline, 20 and oral glucosamine 21 have been reported for OA prevention. In our results, BMP-7 reduced OA progression but did not block progression of OA completely.…”

Section: Discussionmentioning

confidence: 99%

Periodic knee injections of BMP‐7 delay cartilage degeneration induced by excessive running in rats

Sekiya

Tang

Hayashi

et al. 2009

Journal Orthopaedic Research

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Strenuous running of rats enhances mechanical stress on the knee, thereby inducing degeneration of articular cartilage. Bone morphogenetic protein-7 (BMP-7) has an inhibitory effect on cartilage degeneration, suggesting its usefulness for human osteoarthritis patients. However, its mode of administration should be investigated. We examined whether weekly knee injections of BMP-7 delayed the progression of cartilage degeneration. Wistar rats were forced to run 30 km in 6 weeks on a rodent treadmill, and BMP-7 was injected weekly into the knee. Macroscopically and histologically, this strenuous running regimen induced cartilage degeneration. Weekly injections of 250 ng BMP-7 delayed the progression of cartilage degeneration. Immunohistochemically, in the control knee, type II collagen expression decreased, while BMP-7 expression in chondrocytes slightly increased. Interestingly, weekly injection of BMP-7 increased BMP-7 expression even 9 days after the final injection. Disulfate disaccharide keratan sulfate in serum transiently increased in the control group, while it remained at a low level in the BMP-7 group. Weekly BMP-7 injection increased BMP-7 expression in chondrocytes and its effect seemed to last more than 7 days. The effect of BMP-7 could be monitored by serum keratan sulfate concentration. Periodical injections of BMP-7 delayed progression of cartilage degeneration induced by excessive running in rats. Keywords: BMP-7; articular cartilage; strenuous running; keratan sulfate; weekly injection Osteoarthritis (OA) in the knees constitutes an increasingly common medical problem for aging people. 1 Mechanical stress is one of the factors contributing to the progression of OA. Strenuous running of rats enhances mechanical stress on weight bearing joints, inducing OA of the knees. 2,3 This model requires no surgery or drugs, making it possible to detect subtle changes accompanying OA.Bone morphogenetic proteins (BMPs) have a variety of biological effects including enhancement of cartilage repair. 4 Among BMPs, BMP-7 is especially attractive, because it is one of two BMPs already approved for clinical use in various applications by the FDA. Recent data from an anterior cruciate ligament transection model in rabbits demonstrated that continuous intraarticular infusion of BMP-7 had a protective effect on cartilage degeneration, 5 suggesting the possible utility of BMP-7 as a treatment for human OA patients. However, given the challenges associated with clinical delivery by continuous infusion, further consideration should be given to the mode of administration.We speculated that periodic injections of BMP-7 into the knee joint might suppress the loss of cartilage matrix and consequently prevent OA progression. The purpose of this study was to examine whether weekly knee injections of BMP-7 delay development of OA and to investigate the possible mechanisms for this action in a strenuous running model of OA in rats. MATERIALS AND METHODS Strenuous Running of RatsWistar rats at 15-16 weeks of age (Sankyo L...

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Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis

Cited by 156 publications

References 56 publications

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis

Periodic knee injections of BMP‐7 delay cartilage degeneration induced by excessive running in rats

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