Abstract
Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.
Highlights
Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging
Aggrecan degradation facilitated by Matrix metalloproteinase (MMP) and And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) enzymes is a process that occurs within normal and arthritic cartilage, signifying a role for these proteases in normal turnover as well as in arthritis [16], whereas structural changes in aggrecan occur during healthy aging [17]
It was recently shown that MMP-generated aggrecan fragments are involved predominately in normal aggrecan turnover and that their preferred cleavage site is located C-terminal to the interglobular domain (IGD) and that these fragments may have a lesser role in aggrecan degradation in knee injuries and osteoarthritis (OA) in human cartilage [25]
Summary
Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Leflunomide is another DMARD whose effects are unsurprisingly comparable to those of methotrexate [42]; given that it is an immunomodulatory agent that inhibits de novo pyrimidine synthesis, it has the potential to indirectly inhibit ADAMTS4 and ADAMTS5 aggrecanase activity and cartilage destruction by reducing cytokine production (Figure 1).
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