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The Search for Disease-Modifying Osteoarthritis Drugs (DMOADs): The Holy Grail of Osteoarthritis Research
By Nashrah Ahmad, Ph.D. candidate
An old person suffering from joint aches is the image that comes to mind when we come across the term arthritis, a lifestyle affecting condition pervasive within that age group. Osteoarthritis is the most common type of arthritis affecting 27 million people in the US alone, as per NIH statistics. It is predicted that by 2030, approximately 20 percent of the American population will be over 65 with a high risk of developing the disease (1).
Osteoarthritis is mainly characterized by the deterioration of cartilage, leading to severe pain and inflammation in patients. Cartilage is the slippery rubber-like layer between two bones that protects them from rubbing against each other and allows smooth movement. Traditionally, it was considered as wear and tear disease, but research has now established that many chemical mediators and inflammatory cytokines contribute to the pathogenesis by enhancing cartilage degradation. Age, gender, and obesity are some of the associated risk factors and it is not surprising why this disease predominantly affects the elderly. Besides, it is also more common in women due to the fluctuations in hormonal levels.
Unfortunately, there is no cure and the existing therapies provide only temporary pain relief. Several painkillers such as Acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage the symptoms and improve the quality of life. NSAIDs such as diclofenac and naproxen are used for mild to moderate cases, but they are associated with gastrointestinal side effects. In severe cases, opioids such as tramadol are prescribed. Glucocorticoids such as hydrocortisone, when injected into the affected joints, provide short-term improvement. However, none of the current therapies can prevent the progression of the disease.
Therefore, there is an unmet need to develop disease-modifying drugs for this condition. Natural remedies are often talked about, especially those using plant-derived compounds and fruit extracts, which have minimum side effects. Nevertheless, they are not used as the primary therapeutic choice. Fruit extracts, such as pomegranate extract has been shown to reduce pain and discomfort in patients through many scientific studies (2). Pomegranate extract was demonstrated to protect the joints and help in reducing and control inflammation (2). Mesenchymal stem cell therapy is touted as a promising therapeutic strategy and is currently under investigation.
Disease-modifying osteoarthritis drugs (DMOADs) are drugs that prevents structural changes and progression of osteoarthritis. As of now, there is a lack of a licensed drug. According to FDA guidelines, DMOAD refers to a drug that could slow the narrowing of joint space and provide symptomatic relief. Current strategies for developing them mainly focuses on targeting cartilage damage, inflammatory pathways, and subchondral bone remodeling. iNOS inhibitors and protease inhibitors such as MMP inhibitors and ADAMTS inhibitors target the inhibition of cartilage degradation. Another category of candidate DMOADs is anti-inflammatory drugs that target the inhibition of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6.
Inhibition of MAPK Pathway Induced by Proinflammatory Cytokines
Mitogen-activated protein kinase (MAPK) is one of the major pathways involved in the signaling of proinflammatory cytokines and therefore offers a promising therapeutic option. The MAPK pathway includes ERK, JNK/SAPK and p38 family and its inhibition would be a potential cure for the disease. PD 198306, an inhibitor of MEK-1/2 was shown to reduce synovial inflammation and some structural changes associated with osteoarthritis (3). Furthermore, p38 inhibitors have been reported to show anti-inflammatory effects in cartilage and OA animal models. In addition, phenyl-N-tertbutylnitrone (PBN) was shown to inhibit IL-1-induced MMP-13 levels by blocking the JNK pathways (4).
So far, a large number of clinical trials have been carried out to evaluate the efficiency of potential DMOADs; however, until now, an effective DMOAD has been elusive. A possible reason might be the fact that osteoarthritis is a multi-factorial disease and targeting only one pathological aspect may not be enough to tackle this complex disease. Hopefully, in the future, more holistic and combinatorial approaches will help us in finding a disease-modifying drug.
Editor: Rajaneesh K. Gopinath, Ph.D.
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