FK506 ameliorates spontaneous locomotor activity in collagen-induced arthritis: implication of distinct effect from suppression of inflammation

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Abstract

FK506 (tacrolimus), an immunosuppressive drug, improves quality of life (QOL) for patients with rheumatoid arthritis (RA). However, the mechanism of FK506 behind the improvement in QOL is still uncharacterized. To explain the improvement of QOL by FK506, we investigated the effect of FK506 on spontaneous locomotor activity in rats with collagen-induced arthritis (CIA). CIA was induced in 7- to 8-week-old female Lewis rats by immunization with bovine type II collagen. After initiation of paw inflammation (paw swelling, histopathological analysis), CIA rats were therapeutically administered FK506 or methotrexate (MTX) from day 15. Therapeutic treatment with FK506 ameliorated spontaneous locomotor activity without suppressing paw inflammation in CIA rats from day 27. FK506 also improved hyperalgesia and grip strength from day 27. Therapeutic treatment with MTX did not improve spontaneous locomotor activity, and simultaneously did not recover hyperalgesia or grip strength in CIA rats. Our results indicate that spontaneous locomotor activity in CIA rats correlates mainly with hyperalgesia and muscle strength, but not paw inflammation, implying that therapeutic treatment with FK506 ameliorates spontaneous locomotor activity via improvement of hyperalgesia and muscle strength in CIA rats.

Introduction

Rheumatoid arthritis (RA) is a chronic progressive disease that affects quality of life (QOL) [1]. It is an autoimmune disorder of unknown etiology characterized by joint inflammation, leading to disability [2]. Disability, which is quantified by the Health Assessment Questionnaire (HAQ) and is largely associated with the decrease in activity, has a significant impact on QOL in RA patients [3], [4]. Decrease in activity is closely correlated with pain in RA patients, and is often caused and exacerbated by several inflammatory mediators (prostaglandin E2 and inflammatory cytokines) [5], [6], [7]. Decrease in activity is also correlated with a decrease in muscle strength and joint destruction in RA patients [8]. The decrease in muscle strength is improved with anti-inflammatory therapy [9]. Joint destruction is mediated by enzymes such as serine proteases, matrix metalloproteinases and cathepsins, which can be induced by inflammatory cytokines [10]. Pain, the decrease in muscle strength and joint destruction can be induced by inflammation, and subsequently cause a decrease in activity in RA patients. Decreased activity in RA patients includes a problem that puts them at increased risk of additional conditions, such as heart disease, diabetes and high blood pressure [4]. Within 10 years of diagnosis, 50% of patients are too disabled to work and up to 60% of patients with RA face significant disruption to routine activities of daily living [11], [12], [13], [14], [15]. Therefore, it is an important goal to ameliorate the decrease in activity for treatment of RA.

FK506 (tacrolimus) is a new drug used therapeutically for RA patients. FK506 is a calcineurin inhibitor, suppressing activation of T cells by inhibiting nuclear localization of NFAT [16]. FK506 suppresses T cell-derived cytokines [17] and antigen presenting cell-derived inflammatory cytokines, TNFα and IL-1β, in the presence of T cell activation [18], [19]. Clinically, FK506 improves QOL for RA patients who do not tolerate with methotrexate (MTX) well [20], [21]. Phase II studies showed that FK506 significantly improves physical function, pain and joint inflammation in RA patients [20], [21]. Recent studies demonstrate that FK506 suppresses inflammation-related pain in an adjuvant-induced arthritis model when paw edema is suppressed by FK506 [22]. However, the mechanism by which FK506 ameliorates the decrease in activity in RA patients and the relationship between activity and inflammation have not been characterized.

In this study, we investigated the relationship between the effect of FK506 on spontaneous locomotor activity and inflammation, and also compared spontaneous locomotor activity to pain, muscle strength and joint destruction in a collagen-induced arthritis (CIA) rat model.

Section snippets

Drugs

A solid dispersion formulation of FK506 [23] was prepared at Fujisawa Pharmaceutical (Osaka, Japan). MTX was purchased from Sigma (St. Louis, MO, USA). FK506 was suspended in distilled water and MTX was suspended in 0.5% methylcellulose.

Animals

Lewis female rats (130–150 g) in specific pathogen free conditions were purchased from Charles River Japan (Yokohama, Japan) at the age of 6 or 7 weeks. Animals were maintained in groups of 5 for at least 7 days on a 12 h light–dark cycle (lights on from 0700 to

Therapeutic treatment with FK506 recovers body weight in CIA rats

Lewis rats were immunized with type II collagen from day 0, and paw inflammation of CIA rat was characterized with paw swelling and histopathological analysis of ankle joint. Paws of CIA rat swelled, and inflammatory cells infiltrated into ankle joint from day 11 (Fig. 1C, data not shown). On day 35, both infiltration of inflammatory cells into ankle joint and pannus formation were observed in CIA rats (Fig. 2B). The effect of FK506 and MTX in CIA rat was then examined.

When FK506 (3.2 mg/kg) or

Discussion

This study demonstrates that FK506 ameliorates spontaneous locomotor activity in CIA rats via an alternative pathway for suppression of inflammation. Therapeutic treatment with FK506 significantly ameliorated spontaneous locomotor activity in CIA rats from day 27 (Fig. 3). However, FK506 did not improve either paw swelling or infiltration of inflammatory cells into ankle joint until day 35 (Fig. 1, Fig. 2). These results indicate that FK506 ameliorates spontaneous locomotor activity, and that

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