Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis
ABSTRACT 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.
Full-textDOI: · Available from: Martin Lotz, Sep 09, 2014
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ABSTRACT: Periodontal disease is the most common osteolytic disease in humans and is significantly increased by diabetes mellitus. We tested the hypothesis that bacterial infection induces bone loss in diabetic animals through a mechanism that involves enhanced apoptosis. Type II diabetic rats were inoculated with Aggregatibacter actinomycetemcomitans and treated with a caspase-3 inhibitor, ZDEVD-FMK, or vehicle alone. Apoptotic cells were measured with TUNEL; osteoblasts and bone area were measured in H&E sections. New bone formation was assessed by labeling with fluorescent dyes and by osteocalcin mRNA levels. Osteoclast number, eroded bone surface, and new bone formation were measured by tartrate-resistant acid phosphatase staining. Immunohistochemistry was performed with an antibody against tumor necrosis factor-a. Bacterial infection doubled the number of tumor necrosis factor-ae expressing cells and increased apoptotic cells adjacent to bone 10-fold (P < 0.05). Treatment with caspase inhibitor blocked apoptosis, increased the number of osteoclasts, and eroded bone surface (P < 0.05); yet, inhibition of apoptosis resulted in significantly greater net bone area because of an increase in new bone formation, osteoblast numbers, and an increase in bone coupling. Thus, bacterial infection in diabetic rats stimulates periodontitis, in part through enhanced apoptosis of osteoblastic cells that reduces osseous coupling through a caspase-3edependent mechanism. (Am J Pathol 2013, 183: 1928e1935; http://dx.doi.org/10.1016/j.ajpath.2013.08.017) Diabetes is a chronic inflammatory disease characterized by hyperglycemia that affects 26 million Americans. 1 Diabetes has several complications, such as cardiovascular, renal, microvascular, and periodontal diseases. Periodontal disease is one of the most common forms of osteolytic bone disease and one of the most frequent complications of the diabetes. 2 Recent research suggests that the relationship between periodontitis and diabetes is reciprocal. 3,4 People with diabetes are more susceptible to periodontitis, and periodontitis may affect serum glucose levels and contribute to progression of diabetes. 5 Diabetes may contribute to periodontitis because of its effect on inflammation. 6,7 Despite being triggered by bacterial infection, periodontal bone loss is tied to the inflammatory host response, which leads to the generation of prostaglandins and cytokines that stimulate osteoclastogenesis and periodontal bone loss. 8