Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

Picher, Maryse; Graff, Ronald D.; Lee, Greta M.

doi:10.1002/art.11289

Cited by 24 publications

(13 citation statements)

References 174 publications

(176 reference statements)

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“…The chondrocytes, the unique cell type residing in cartilage [54,55], can release PGE 2 [56], a major contributor of inflammatory pain in arthritis conditions, that subsequently acts through a variety of prostanoids receptors expressed in peripheral sensory neurons and spinal cord [57]. A previous in vitro study showed that ATP and α,β-meATP (P2X3 agonist, [14] increase PGE 2 production, an effect that was blocked by the selective P2X3 and P2X2/3 receptors antagonist A317491, indicating a role of P2X3 receptors in PGE 2 release by chondrocytes [18].…”

Section: Discussionmentioning

confidence: 99%

P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

et al. 2016

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“…Once released from the cell, ATP may activate P2 receptors triggering intracellular Ca 2+ signalling cascades. Indeed, the activation of P2 receptors following mechanically induced ATP release or addition of endogenous ATP has been shown to have an anabolic effect, with an upregulation in proteoglycan and collagen synthesis and cell proliferation (Kaplan et al 1996;Brown et al 1997;Croucher et al 2000;Picher et al 2003;Millward-Sadler et al 2004;Chowdhury & Knight, 2006). Furthermore, there is a corresponding down-regulation in MMP expression and nitric oxide release.…”

Section: Discussionmentioning

confidence: 99%

Articular chondrocytes express connexin 43 hemichannels and P2 receptors – a putative mechanoreceptor complex involving the primary cilium?

Knight¹,

McGlashan²,

Garcia³

et al. 2009

Journal of Anatomy

120

114

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Mechanical loading is essential for the health and homeostasis of articular cartilage, although the fundamental mechanotransduction pathways are unclear. Previous studies have demonstrated that cyclic compression up-regulates proteoglycan synthesis via an intracellular Ca 2+ signalling pathway, mediated by the release of ATP. However, the mechanism(s) of ATP release has not been elucidated. The present study examines expression of the putative mechanosensitive ATP-release channel, connexin 43 and whether it is expressed on the chondrocyte primary cilium, which acts as a mechanosensor in a variety of other cell types. In addition the study characterized the expression of a range of purine receptors through which ATP may activate downstream signalling events controlling cell function. Bovine articular chondrocytes were isolated by sequential enzyme digestion and seeded in agarose constructs.To verify the presence of functional hemichannels, Lucifer yellow (LY) uptake into viable cells was quantified following treatment with a hemichannel agonist (EGTA) and antagonist (flufenamic acid). LY uptake was observed in 45% of chondrocytes, increasing to 83% following EGTA treatment ( P < 0.001). Treatment with the hemichannel blocker, flufenamic acid, significantly decreased LY uptake to less than 5% with and without EGTA. Immunofluorescence and confocal microscopy confirmed the presence of primary cilia and the expression of connexin 43. Approximately 50% of bovine chondrocyte primary cilia were decorated with connexin 43. Human chondrocytes in situ within cartilage explants also expressed connexin 43 hemichannels. However, expression was confined to the upper 200 μ m of the tissue closest to the articular surface. Immunofluorescence revealed the expression of a range of P2X and P2Y receptor subtypes within human articular cartilage. In conclusion, the expression of functional hemichannels by articular chondrocytes may represent the mechanism through which mechanical loading activates ATP release as part of a purinergic mechanotransduction pathway. Furthermore, the expression of connexin 43 on the chondrocyte primary cilium suggests the possible involvement of the cilium in this pathway.

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“…More recently, we have implicated a similar autoregulatory pathway in differentiating cells of chicken chondrogenic cell cultures, with P2X4 ionotropic purinergic receptor being the most likely candidate [10,11]. Given that CPCs were originally derived from OA-affected articular cartilage wherein extracellular nucleotides released along with inflammatory mediators may be considered as important ligands of purinergic receptors [41], we aimed to study whether CPCs were able to respond to nucleotide stimulation by P1 and/or P2 receptor activation.…”

Section: Purinergic Signalling In Cpcs and Autocrine/paracrine Regulamentioning

confidence: 99%

Purinergic signalling is required for calcium oscillations in migratory chondrogenic progenitor cells

Matta

Fodor

Miosge

et al. 2014

Pflugers Arch - Eur J Physiol

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Osteoarthritis (OA) is the most common form of chronic musculoskeletal disorders. A migratory stem cell population termed chondrogenic progenitor cells (CPC) with in vitro chondrogenic potential was previously isolated from OA cartilage. Since intracellular Ca 2+ signalling is an important regulator of chondrogenesis, we aimed to provide a detailed understanding of the Ca 2+ homeostasis of CPCs. In this work, CPCs immortalised by lentiviral administration of the human telomerase reverse transcriptase (hTERT) and grown in monolayer cultures were studied. Expressions of all three IP3Rs were confirmed, but no RyR subtypes were detected. Ca 2+ oscillations observed in CPCs were predominantly dependent on Ca 2+ release and store replenishment via store-operated Ca 2+ entry; CPCs express both STIM1 and Orai1 proteins. Expressions of adenosine receptor mRNAs were verified, and adenosine elicited Ca 2+ transients. Various P2 receptor subtypes were identified; P2Y1 can bind ADP; P2Y4 is targeted by UTP; and ATP may evoke Ca 2+ transients via detected P2X subtypes, as well as P2Y1 and P2Y2. Enzymatic breakdown of extracellular nucleotides by apyrase completely abrogated Ca 2+ oscillations, suggesting that an autocrine/paracrine purinergic mechanism may drive Ca 2+ oscillations in these cells.As CPCs possess a broad spectrum of functional molecular elements of Ca 2+ signalling, Ca 2+ -dependent regulatory mechanisms can be supposed to influence their differentiation potential.

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Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

Cited by 24 publications

References 174 publications

P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

Articular chondrocytes express connexin 43 hemichannels and P2 receptors – a putative mechanoreceptor complex involving the primary cilium?

Purinergic signalling is required for calcium oscillations in migratory chondrogenic progenitor cells

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