Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates

Baroja‐Mazo, Alberto; Pelegrı́n, Pablo

doi:10.1155/2012/408242

Cited by 34 publications

(21 citation statements)

References 67 publications

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“…As bisphosphonates are reported to have anti-inflammatory actions,30 31 such effects may play a role in an immediate analgesic benefit, as distinct from that which might arise as a consequence of osteochondral structural alteration, and explain why analgesic benefits in this study did not persist beyond the period of drug use.…”

Section: Discussionmentioning

confidence: 81%

Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative

et al. 2013

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Objectives: Bisphosphonates have some reported beneficial effects in treating osteoarthritis (OA). This study examined the effects of bisphosphonate use on symptoms and structural progression of knee OA in participants from the NIH Osteoarthritis Initiative cohort. Methods:People with typical OA trial entry criteria (KL2/3, minimum joint space width (mJSW) 2.5-5.0mm and pain ≥4 on a numerical rating scale [NRS]) were classified as bisphosphonate users (3 of the 5 years; n=55) or non-users (no use in the preceding 5 years or during follow-up; n=268). Annual data over 4 years were analysed using linear mixed modelling and generalised estimating equations.Results: Bisphosphonate compliance was 85% at year 1, reducing to 76% by year 4. NRS pain scores were significantly reduced among bisphosphonate users at years 2 and 3 (Year 3, -0.9 vs -2.2, p=0.004), though not year 4, after adjustment for baseline pain and analgesic use. Differences in WOMAC pain and disability scores did not reach statistical significance at any time point. There was a trend to less joint space narrowing in bisphosphonate users over time (Year 4, 0.51mm vs 0.29mm; p=0.06). Zoledronic acid has been reported effective in reducing knee pain and the size of BMLs. Conclusions[7]However, though risedronate (15 mg) reduced markers of cartilage degradation and bone resorption, it did not achieve WOMAC symptom reduction or slowing of radiologic progression of joint space narrowing over 2 years [19,20]. Page 4The NIH Osteoarthritis Initiative (OAI) provides a large, comprehensive dataset which permits exploration of the effects of bisphosphonates over a number of years.We aimed to examine the effect of bisphosphonate use on OA symptom and structural outcomes in people selected from the OAI cohort for typical OA trial inclusion criteria and followed for 4 years. PATIENTS AND METHODS Study design, setting and participantsData used in the preparation of this article were obtained from the Osteoarthritis Initiative (OAI) cohort, a publicly available multi-centre population-based observational cohort study of knee OA which is available for public access at http://www.oai.ucsf.edu/. Specific datasets used are detailed Supplementary Table 1. The OAI comprises data on persons aged 45-79 years within three sub-cohorts, the Progression group (persons with existing knee OA; n=1,390), the Incidence group (persons with risk factors for knee OA; n=3,284) and the non-exposed control group (n=122) [21]. Both knees of 4796 participants were studied annually using 3T MR imaging (not used in these analyses) and fixed flexion radiography [22,23]at baseline, 1, 2, 3 and 4 years follow-up.Persons were excluded from the OAI if they had inflammatory arthritis, severe joint space narrowing (JSN) in both knees, unilateral knee joint replacement and severe JSN in the contralateral knee, inability to undergo MRI, or to provide a blood sample, required use of walking aids excepting a single straight cane ≤50% of the time, or were unwilling to provide informed consent. Pat...

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Section: Discussionmentioning

confidence: 81%

Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative

et al. 2013

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“…Indeed, increased TF + MP levels correlate with hypercoagulability in endotoxemic mice (79), and extracellular TRX levels are significantly elevated in plasma of sepsis patients (80). Similarly, P2RX7 signaling is implicated in rheumatoid arthritis (81), and high levels of extracellular TRX (82,83) as well as of TF + MPs (84) are detected in the synovial fluids of patients. Notably, the TRXR inhibitor auranofin is efficacious in the treatment of rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1–mediated pathway promotes generation of thromboinflammatory microparticles

Rothmeier¹,

Marchese²,

Petrich³

et al. 2015

J. Clin. Invest.

104

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“…Proinflammatory actions of P2X7 mediated by macrophages contribute to bone and cartilage diseases (Baroja-Mazo and Pelegrín, 2012). Our results show that the P2X7-specific antagonist A438079 or TIIAS largely inhibited the ATP-induced Ca 21 influx and YO-PRO-1 uptake in hMDM.…”

Section: Discussionmentioning

confidence: 63%

Tanshinone II A Sulfonate, but Not Tanshinone II A, Acts as Potent Negative Allosteric Modulator of the Human Purinergic Receptor P2X7

Kaiser

Sobottka

Fischer

et al. 2014

J Pharmacol Exp Ther

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Tanshinone II A sulfonate (TIIAS) was identified as a potent, selective blocker of purinergic receptor P2X7 in a compound library screen. In this study, a detailed characterization of the pharmacologic effects of TIIAS on P2X7 is provided. Because TIIAS is a derivative of tanshinone II A (TIIA) and both compounds have been used interchangeably, TIIA was included in some assays. Fluorometric and electrophysiologic assays were used to characterize effects of TIIAS and TIIA on recombinantly expressed human, rat, and mouse P2X7. Results were confirmed in human monocyte-derived macrophages expressing native P2X7. In all experiments, involvement of P2X7 was verified using established P2X7 antagonists. TIIAS, but not TIIA, reduces Ca 21 influx via human P2X7 (hP2X7) with an IC 50 of 4.3 mM. TIIAS was less potent at mouse P2X7 and poorly inhibited rat P2X7. Monitoring of YO-PRO-1 uptake confirmed these findings, indicating that formation of the hP2X7 pore is also suppressed by TIIAS. Electrophysiologic experiments revealed a noncompetitive mode of action. TIIAS time-dependently inhibits hP2X7 gating, possibly by binding to the intracellular domain of the receptor. Inhibition of native P2X7 in macrophages by TIIAS was confirmed by monitoring Ca 21 influx, YO-PRO-1 uptake, and release of the proinflammatory cytokine interleukin-1b. Fluorometric experiments involving recombinantly expressed rat P2X2 and human P2X4 were conducted and verified the compound's selectivity. Our data suggest that hP2X7 is a molecular target of TIIAS, but not of TIIA, a compound with different pharmacologic properties.

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Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates

Cited by 34 publications

References 67 publications

Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative

Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative

Caspase-1–mediated pathway promotes generation of thromboinflammatory microparticles

Tanshinone II A Sulfonate, but Not Tanshinone II A, Acts as Potent Negative Allosteric Modulator of the Human Purinergic Receptor P2X7

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