Genetic ablation of adenosine receptor A3 results in articular cartilage degeneration

Shkhyan, Ruzanna; Lee, Siyoung; Gullo, Francesca; Li, Lei; Peleli, Maria; Carlström, Mattias; Chagin, Andrei S.; Banks, Nicholas W.; Limfat, Sean; Liu, Nancy Q.; Evseenko, Denis

doi:10.1007/s00109-018-1680-3

Cited by 15 publications

(17 citation statements)

References 39 publications

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“…The anti-inflammatory properties of stimulating both adenosine receptors 28 likely www.nature.com/scientificreports/ play a critical role in preventing progression of osteoarthritis in these models, particularly the monoiodoacetateinduced model of osteoarthritis which is characterized by acute inflammatory changes. Both A2AR and A3R stimulation inhibit chondrocyte production of catabolic proteins 11,14,27,29,30 associated with cartilage destruction but, to date, only A2AR stimulation of chondrocytes induces production of cartilage matrix, as shown here.…”

Section: Discussionsupporting

confidence: 62%

“…Although it is likely, based on the efficacy of the lipo-CGS21680 (a selective A2AR agonist) treatments to promote cartilage formation, that stimulation of the A2AR is principally responsible for the improvement in osteoarthritis observed here it is possible that other adenosine receptors are also involved in this therapeutic effect. Deletion of both A2AR and A3R have been shown to lead to osteoarthritis 11,27 and it is likely that the homeostatic role of adenosine in cartilage and chondrocytes is mediated by both receptors. Interestingly osteoarthritis becomes evident within 6 months of age in A2AR deficient mice but has only been described in aged mice lacking A3R, suggesting that the A2AR is more critical for maintenance of chondrocyte homeostasis throughout life, whereas loss of the A3R exacerbates the effects of age on cartilage.…”

Section: Discussionmentioning

confidence: 99%

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Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

Corciulo

Castro

Coughlin

et al. 2020

Sci Rep

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Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis and here we report that injection of liposomal suspensions of either adenosine or a selective A2AR agonist, CGS21680, significantly reduced oA cartilage damage in a murine model of obesity-induced oA. the same treatment also improved swelling and preserved cartilage in the affected knees in a rat model of established posttraumatic OA (PTOA). Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with PTOA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone. Studies in vitro and in affected joints demonstrated that A2AR ligation increased the nuclear P-SMAD2/3/P-SMAD1/5/8 ratio, a change associated with repression of terminal chondrocyte differentiation. These results strongly suggest that targeting the A2AR is an effective approach to treat oA. Osteoarthritis (OA) is a common disease affecting 151 million people worldwide and its incidence is expected to increase in industrialized countries due to aging and increased obesity of the population, a condition that together with previous joint injury represent the most common risk factors 1. OA can affect any joint, but most commonly affects the knee, hip and hand. The prevalence of OA is greatest in the knee joint, in both women (47%) and men (40%), and there is no therapy currently available that can reverse or halt the progression of OA 2,3 short of total joint replacement. Total knee replacements are the most common joint surgeries and it has been estimated that there will be a fivefold increase in the number of patients undergoing this surgical procedure up to 3.5 million by 2030 4,5. In search of effective therapies, a number of different approaches have been taken including a focus on both growth factors, such as transforming growth factor-beta (TGFβ), and other molecular pathways involved in regulating cartilage development and homeostasis. TGFβ molecular signaling exerts dual and opposing roles in cartilage and chondrocyte health depending on the receptor and signal activated downstream. It has been shown that inhibition of high levels of systemic TGFβ attenuates anterior cruciate ligament rupture-induced OA in mice by preventing loss of proteoglycan from the cartilage and protecting the subchondral bone from structural alteration 6. Moreover, the effect of TGFβ on joint health depends on which receptor it binds. Activation of

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

Corciulo

Castro

Coughlin

et al. 2020

Sci Rep

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“…The replacement of adenosine in the intraarticular space has shown delayed osteoarthritis progression in a rat model of post-traumatic osteoarthritis through a molecular mechanism involving A2A adenosine receptor activation (Corciulo et al, 2017). We also demonstrated that mice lacking A2A adenosine receptors develop spontaneous bone and cartilage features of OA associated with reduced motor activity and Shkhyan and colleagues demonstrated that ablation of A3 receptors results in OA development in aged mice (Corciulo et al, 2017;Shkhyan et al, 2018) (Figure 3).…”

Section: P1 Receptorssupporting

confidence: 54%

Signaling of the Purinergic System in the Joint

Corciulo

Cronstein

2020

Front. Pharmacol.

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The joint is a complex anatomical structure consisting of different tissues, each with a particular feature, playing together to give mobility and stability at the body. All the joints have a similar composition including cartilage for reducing the friction of the movement and protecting the underlying bone, a synovial membrane that produces synovial fluid to lubricate the joint, ligaments to limit joint movement, and tendons for the interaction with muscles. Direct or indirect damage of one or more of the tissues forming the joint is the foundation of different pathological conditions. Many molecular mechanisms are involved in maintaining the joint homeostasis as well as in triggering disease development. The molecular pathway activated by the purinergic system is one of them.The purinergic signaling defines a group of receptors and intermembrane channels activated by adenosine, adenosine diphosphate, adenosine 5'-triphosphate, uridine triphosphate, and uridine diphosphate. It has been largely described as a modulator of many physiological and pathological conditions including rheumatic diseases. Here we will give an overview of the purinergic system in the joint describing its expression and function in the synovium, cartilage, ligament, tendon, and bone with a therapeutic perspective.

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“…A3R knockout (KO) mice develop progressive loss of articular cartilage. Agonists for A3R downregulate key genes implicated in OA pathology, such as RUNX2 ( 151 ). In a recent study CF101, a highly selective A3R agonist, was orally administered twice daily to monosodium iodoacetate OA-induced rats.…”

Section: Purinergic System In Oa and Modulation By Metainflammationmentioning

confidence: 99%

“…In the case of excessive joint motion, which leads to excessive activation of CD73 via hypoxia inducible factor (HIF)-1α, extracellular adenosine accumulates. The consequent activation of the low-affinity A2BR seems to play a harmful role in cartilage homeostasis, possibly due to its capacity of stimulating inflammatory pathways involving MAPK ( 128 , 151 ). In OA, as a low-grade chronic inflammatory disease, increased extracellular adenosine levels may switch selectivity of receptor binding toward A2BR, generating hyperalgesia ( 138 ) ( Table 2 ).…”

Section: Purinergic System In Oa and Modulation By Metainflammationmentioning

confidence: 99%

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

et al. 2020

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Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.

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Genetic ablation of adenosine receptor A3 results in articular cartilage degeneration

Cited by 15 publications

References 39 publications

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

Signaling of the Purinergic System in the Joint

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

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