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Transl Res. 2018 Sep;199:24-38. doi: 10.1016/j.trsl.2018.04.001. Epub 2018 May 17.

Prophylactic and therapeutic activity of alkaline phosphatase in arthritic rats: single-agent effects of alkaline phosphatase and synergistic effects in combination with methotrexate.

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Amsterdam Rheumatology and immunology Center, VU University Medical Center, Amsterdam, The Netherlands.
Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Department of Chemistry, Purdue University, West Lafayette, Indiana.
Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Rheumatology, KIMS Hospital, Kent, United Kingdom.
AMRIF BV, Wageningen, The Netherlands.
Amsterdam Rheumatology and immunology Center, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:


Alkaline phosphatase (AP) is a gate-keeper of innate immune system responses by detoxifying inflammation triggering moieties released from endogenous and external sources. We examined whether AP's broad mechanism of action constitutes a safe therapeutic, either as single agent or combined with methotrexate (MTX), for chronic inflammatory disorders, for example, rheumatoid arthritis (RA). A rat model for RA was used with repeated intra-articular methylated bovine serum albumin (mBSA) injections in 1 knee ("arthritic" knee), with the contralateral knee serving as internal control. AP (200 µg, subcut) was administered before mBSA injections (prophylactic setting) or after arthritis induction (therapeutic setting) or combined with MTX (0.3 mg/kg or 1 mg/kg; intraperitoneally). As end point of treatment outcome, macrophage infiltration in knees, liver, and spleen was assessed by immunohistochemistry (ED1 and ED2 expression), immunofluoresence (macrophage marker folate receptor-β [FRβ]), and [18F]fluoro-polyethylene glycol-folate positron emission tomography (PET) (macrophage imaging) and ex vivo tissue distribution. Single-agent AP treatment and combinations with MTX were well tolerated. Both prophylactic and therapeutic AP markedly reduced synovial macrophage infiltration in arthritic knees (ED1: 3.5- to 4-fold; ED2: 3.5- to 6-fold), comparable with MTX treatment. AP-MTX combinations slightly improved on single agent effects. PET monitoring and ex vivo tissue distribution studies corroborated the impact of AP, MTX, and AP-MTX on reducing synovial macrophage infiltration. Beyond localized articular effects, AP also revealed systemic anti-inflammatory effects by a 2-fold reduction of ED1, ED2, and FRβ+ macrophages in liver and spleen of arthritic rats. Collectively, single-agent AP and AP combined with MTX elicited local and systemic anti-arthritic activity in arthritic rats.

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