Correlation of changes in pain intensity with synovial fluid adenosine triphosphate levels after treatment of patients with osteoarthritis of the knee with high-molecular-weight hyaluronic acid
“…Further, they are also consistent with human studies showing that extracellular ATP is often found in the synovial fluid of patients with arthropathies [52,53]. …”
Osteoarthritis (OA) is a degenerative and progressive disease, characterized by cartilage breakdown and by synovial membrane inflammation, which results in disability, joint swelling and pain. The purinergic P2X3 and P2X2/3 receptors contribute to development of inflammatory hyperalgesia, participate in arthritis processes in the knee joint and are expressed in chondrocytes and nociceptive afferent fibers innervating the knee joint. In this study, we hypothesized that P2X3 and P2X2/3 receptors activation by endogenous ATP (adenosine 5′-triphosphate) induces articular hyperalgesia in the knee joint of male and female rats through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration. We found that the blockade of articular P2X3 and P2X2/3 receptors significantly attenuated carrageenan-induced hyperalgesia in the knee joint of male and estrus female rats in a similar manner. The carrageenan-induced knee joint inflammation increased the expression of P2X3 receptors in chondrocytes of articular cartilage. Further, the blockade of articular P2X3 and P2X2/3 receptors significantly reduced the increased concentration of TNF-α, IL-6 and CINC-1 and the neutrophil migration induced by carrageenan. These findings indicate that P2X3 and P2X2/3 receptors activation by endogenous ATP is essential to hyperalgesia development in the knee joint through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration.
“…Further, they are also consistent with human studies showing that extracellular ATP is often found in the synovial fluid of patients with arthropathies [52,53]. …”
Osteoarthritis (OA) is a degenerative and progressive disease, characterized by cartilage breakdown and by synovial membrane inflammation, which results in disability, joint swelling and pain. The purinergic P2X3 and P2X2/3 receptors contribute to development of inflammatory hyperalgesia, participate in arthritis processes in the knee joint and are expressed in chondrocytes and nociceptive afferent fibers innervating the knee joint. In this study, we hypothesized that P2X3 and P2X2/3 receptors activation by endogenous ATP (adenosine 5′-triphosphate) induces articular hyperalgesia in the knee joint of male and female rats through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration. We found that the blockade of articular P2X3 and P2X2/3 receptors significantly attenuated carrageenan-induced hyperalgesia in the knee joint of male and estrus female rats in a similar manner. The carrageenan-induced knee joint inflammation increased the expression of P2X3 receptors in chondrocytes of articular cartilage. Further, the blockade of articular P2X3 and P2X2/3 receptors significantly reduced the increased concentration of TNF-α, IL-6 and CINC-1 and the neutrophil migration induced by carrageenan. These findings indicate that P2X3 and P2X2/3 receptors activation by endogenous ATP is essential to hyperalgesia development in the knee joint through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration.
“…Furthermore, a recent study shows the activation of pyroptosis in OA fibroblast‐like synoviocytes by ATP together with TLR‐4 ligands . Finally, ATP increases pain sensitivity (hyperalgesia) via binding to the purinergic P2X3 and P2X2/3 receptors .…”
Summary
Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease‐modifying therapy is available. For a long time, OA was considered a non‐inflammatory disease that was the result of ‘wear‐and‐tear’ and abnormal mechanics, and therefore many considered the term ‘osteoarthritis’ a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low‐grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted.
“…2), is able to activate arthritic knee-joint afferent fibers [55] and is present in arthritic patient synovial fluid [56, 57] as well as at tumor sites [58]. Recently, it was reported that in patients with arthritic knee joints [59], synovial ATP content was both positively associated with symptom severity and seen to decline during symptom ameliorating therapy with intra-articular hyaluronic acid.Fig. 2Pain from damaged and strained joints and other musculoskeletal structures chronically impacts the lives of a vast number of individuals.…”
Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention.
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