A drug that prevents blood clots reduced pain and improved mobility in mice and monkeys with knee osteoarthritis. The approach seems to partly work by reducing inflammatory signals that degrade cartilage.
Osteoarthritis is caused by the wear and tear of cartilage that cushions the ends of bones, leading to inflammation, pain and stiffness. It affects people worldwide. Painkillers and anti-inflammatory drugs can relieve symptoms, but no approved drugs halt or slow worsening of the disease.
鈥淲e have nothing to offer our patients apart from suggesting weight loss, or offering drugs that provide pain relief,鈥� says at the University of Oxford, who wasn鈥檛 involved in the study.
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It is widely thought that inflammatory molecules called TNF-alpha and IL-1-beta drive inflammation that worsens osteoarthritis. This has led to clinical trials testing drugs that target either of these molecules. But these have been unsuccessful, potentially because these molecules compensate for each other when one is blocked, according to at Yale University and his colleagues.
To explore whether targeting both molecules may be more effective, the researchers surgically removed part of the cartilage in the left knee joints of eight monkeys to mimic wear and tear that triggers osteoarthritis.
A month later, four of the monkeys took a daily dose of a drug called dabigatran, mixed into their food. Dabigatran is commonly used to prevent blood clots in people at increased risk of strokes, but has also been shown to block inflammatory signals via both TNF-alpha and IL-1-beta. The remaining monkeys ate their usual food as a control.
After seven months, MRI scans revealed that the left-knee cartilage in monkeys on dabigratan was about 60 per cent thicker, on average, compared to the control monkeys. This suggests that the drug reduced cartilage damage, slowing the progression of osteoarthritis, says Liu.
Monkeys on dabigratan also had a roughly 15 per cent greater range of motion in their left knee than the control monkeys. 鈥淢onkeys receiving dabigatran showed a more natural walking pattern and a greater range of knee movement,鈥� says Liu. 鈥淭hese improvements are consistent with reduced joint stiffness and discomfort.鈥�
In further experiments, the team confirmed their findings in mice with surgically-induced knee osteoarthritis, which also revealed that dabigratan reduced inflammation in the knee by about 60 per cent.
The findings suggest dabigratan could slow the progression of osteoarthritis in people. 鈥淭hey鈥檝e used the best [animal] models we have of osteoarthritis,鈥� says Vincent. 鈥淚f the findings can be replicated by another research group, you would certainly consider trying a small clinical trial,鈥� she says.
But it is unclear whether the approach can reverse damage that has already occurred, says Liu. Another limitation is that giving people a drug that reduces blood clotting puts them at greater risk of bleeds, so the researchers are now developing drugs that target TNF-alpha and IL-1-beta without reducing clotting, which they will test in mice before any clinical trials, says Liu.
However, Vincent says suggest that inhibiting molecules involved in blood clotting may relieve osteoarthritis symptoms, which might mean that some of dabigratan鈥檚 benefits are due to its anti-clotting, rather than anti-inflammatory, effect. Further research that compares dabigatran with drugs that target TNF-alpha and IL-1-beta without the clotting effects should help to clarify this, she says.
Science Translational Medicine DOI: 10.1126/scitranslmed.aec8494
