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AB0082 Alkaline phosphatase elicits prophylactic and therapeutic effects in arthritic rats
  1. DMSH Chandrupatla1,
  2. CFM Molthoff2,
  3. E Elshof2,
  4. W Ritsema2,
  5. M Verlaan2,
  6. R Vos2,
  7. A Hammond3,
  8. AA Lammertsma2,
  9. CJ van der Laken1,
  10. R Brands4,
  11. G Jansen1
  1. 1Amsterdam Rheumatology and immunology Centre – location VUmc
  2. 2Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands
  3. 3KIMS Hospital, Kent, United Kingdom
  4. 4AMRIF BV, Wageningen, Netherlands

Abstract

Background Alkaline phosphatase (AP) functions as a gate-keeper of the innate immune system [1] by detoxifying inflammation triggering moieties (ITMs). As an ectophosphatase, AP thus acts extracellularly by dephosphorylating ITMs that originate and are released from endogenous sources, e.g. by converting ADP and ATP nucleotides into adenosine to establish a key signalling anti-inflammatory effect. Consequently, AP activity prevents the production of pro-inflammatory cytokines by activated leucocytes and their downstream effects. Due to its broad mechanism of action, AP may potentially serve as an attractive therapeutic moiety in chronic inflammatory disorders, including rheumatoid arthritis (RA).

Objectives To examine the anti-arthritic effects of prophylactic and therapeutic AP interventions in arthritic rats.

Methods Wistar rats were immunized twice with methylated bovine serum albumin (mBSA), followed by local arthritis induction (intra-articular (i.a.) mBSA injection with 3 repeated injections) in the right knee (arthritic knee) with the contralateral left knee serving as internal control [2]. Interventions were performed using 200 μg human recombinant placental AP, administered subcutaneously, either before i.a. mBSA injections (2x, every 3 days, 2 rats/group; prophylactic setting) or after arthritis induction (4x, every 3 days, 4 rats/group; therapeutic setting). After ex vivo tissue distribution, knees were excised, fixed, decalcified and paraffin-embedded. Knee sections were examined for synovial macrophage infiltration by immunohistochemistry with ED1 (∼CD68) and ED2 (∼CD163) macrophage specific antibodies. Results were compared with untreated arthritic rats and arthritic rats receiving MTX therapy (1 mg/kg, intraperitoneally, 4x, every 3 days, 4 rats/group).

Results Prophylactic and therapeutic schedules of AP treatment were well tolerated and reduced knee swelling comparable with MTX treatment. Following AP prophylactic intervention, synovial macrophage infiltration in the arthritic knees was reduced 4-fold (ED1) and 6-fold (ED2) when compared with affected knees of untreated arthritic rats, approaching macrophage counts in contralateral (non-arthritic) knees of AP treated rats. Therapeutic AP interventions resulted in 3.5-fold lower synovial infiltration of both ED1 and ED2 macrophages in arthritic knees, comparable with effects of MTX treatment.

Conclusions AP, both as prophylactic and as therapeutic intervention, demonstrated favourable anti-arthritic efficacy in a rat model of arthritis. These studies warrant further preclinical and clinical evaluation as a putative novel therapeutic entity for arthritis.

References

  1. Pike AF et al, Biochim Biophys Acta (2013);1832:2044–2056.

  2. Chandrupatla DM et al, Biomed Res Int. (2015), 509295.

References

Disclosure of Interest None declared

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