Osteoarthritis (OA) is a pervasive and incapacitating musculoskeletal disorder that affects approximately 300 million people worldwide. Its cardinal symptom is chronic pain, which, if inadequately managed, can lead to reduced joint function, compromised sleep quality, and long-term disability. Conventional pharmacological treatments such as nonsteroidal anti-inflammatory drugs and opioids often fall short in providing adequate pain relief and may entail undesirable side effects with chronic use. Consequently, OA pain management remains a formidable challenge that necessitates the development of disease-specific analgesics.
Peripheral nociceptive input plays a pivotal role in OA pain, as evidenced by reduced pain following intra-articular lidocaine injections. Studies in rodent models have further underlined the significance of nociceptor activity in OA pain, showing early sensitization of knee-innervating neurons. Consequently, identifying key molecules implicated in OA pain development and targeting them for treatment has become a priority. One such target is nerve growth factor (NGF), targeting of which with sequestering monoclonal antibodies has shown promise in preclinical models and clinical trials, but has faced challenges in humans due to the risk of inducing rapid OA progression; anti-NGF antibodies are however licensed for treating OA in cats and dogs.
In the quest for disease-modifying OA therapies, mesenchymal stem/stromal cell (MSC) therapy has emerged as a promising avenue. Clinical trials have demonstrated pain relief and improved joint function in OA patients receiving MSC treatment. MSCs exert their effects through paracrine mechanisms, leading to analgesic and anticatabolic effects in OA-affected joints. However, it remains unclear whether MSCs directly affect nociceptive input. To address this gap in knowledge, a recent study led by Professor Ewan St. John Smith and his team (Dr Minji Ai, Dr William Hotham, Dr Luke Pattison, Qingxi Ma, and Dr Frances Henson) at the University of Cambridge investigated the potential of both MSCs and extracellular vesicles derived from MSCs (MSC-EVs) in modulating nociception in OA-affected joints.
The authors used a mouse model of destabilization of the medial meniscus (DMM) to induce OA-like joint pathology. They assessed pain-related behaviors using various tests, including the rotarod test, burrowing behavior analysis, and continuous monitoring of activity patterns. Their results demonstrated that untreated DMM-operated mice exhibited pain-related behavioral changes, such as reduced rotarod performance, decreased burrowing activity, and disrupted rest patterns during the lights-on period. These changes indicated the presence of chronic pain, akin to the sleep disturbances observed in OA patients.
The researchers found that DMM-operated mice treated with either MSCs or MSC-EVs did not exhibit significant differences in pain-related behaviors compared to the sham group. These treated mice displayed similar rotarod performance, burrowing activity, and rest patterns during the lights-on period as the sham-operated mice. Moreover, no significant improvements in joint damage were observed in MSC- or MSC-EV–treated DMM-operated mice, suggesting that the pain relief provided by these treatments was not due to a reduction in gross joint pathology. To investigate the potential underlying mechanisms, the researchers then examined the excitability of knee-innervating dorsal root ganglion (DRG) sensory neurons. These neurons play a pivotal role in nociception, and their hyperexcitability has been associated with driving joint pain. In untreated DMM-operated mice, knee-innervating DRG neurons displayed hyperexcitability characterized by depolarized resting membrane potential, reduced action potential firing threshold, and altered action potential properties. This hyperexcitability was normalized in both MSC- and MSC-EV–treated DMM-operated mice. Furthermore, they explored if MSC-EVs can normalize NGF-induced DRG neuron hyperexcitability in vitro. In a series of experiments, DRG neurons were exposed to NGF, leading to hyperexcitability. However, when DRG neurons were incubated with MSC-EVs together with NGF, hyperexcitability did not occur, indicating that MSC-EVs can counteract NGF-induced hyperexcitability.
In conclusion, the study led by Dr Minji Ai offers a compelling glimpse into the future of pain management in OA and potentially other chronic pain conditions. By targeting nociceptive pathways through the modulation of sensory neuron excitability, MSCs and MSC-EVs represent a new frontier in pain therapeutics, offering hope for millions of individuals suffering from debilitating pain associated with OA and other chronic pain disorders. One key point of future research for Professor Ewan St. John Smith’s team is to determine how MSC-EVs evoke their analgesic effects. Further research and clinical trials are warranted to harness the full potential of these innovative approaches and bring relief to those in need.
Ai M, Hotham WE, Pattison LA, Ma Q, Henson FMD, Smith ESJ. Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis. Arthritis Rheumatol. 2023;75(3):352-363. doi: 10.1002/art.42353.