Research Article
The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice

https://doi.org/10.1016/j.jnutbio.2017.10.010Get rights and content

Abstract

Titanium dioxide (TiO2) is a common component of orthopedic prosthesis. However, prosthesis wear releases TiO2, which induces inflammation and osteolysis in peri-prosthetic tissues. Quercetin is a flavonoid widely present in human diet, which presents biological activities such as antinociceptive, anti-inflammatory and antioxidant effects. Therefore, the effect of intraperitoneal treatment with quercetin in TiO2-induced arthritis model was evaluated. In the first set of experiments, mice received injection of TiO2 (0.1–3 mg/knee joint) and articular mechanical hyperalgesia, edema and histopathology analysis were performed in a 30 days protocol. The dose of 3 mg of TiO2 showed the most harmful effect, and was chosen to the following experiments. Subsequently, mice received 3 mg of TiO2 followed by post-treatment with quercetin during 30 days. Quercetin (10–100 mg/kg) inhibited in a dose-dependent manner TiO2-induced knee joint mechanical hyperalgesia, edema and leukocyte recruitment and did not induce damage in major organs such as liver, kidney and stomach. The dose of 30 mg/kg was chosen for the subsequent analysis, and reduced histopathological changes such as leukocyte infiltration, vascular proliferation and synovial hyperplasia (pannus formation) on day 30 after TiO2 challenge. The protective analgesic and anti-inflammatory mechanisms of quercetin included the inhibition of TiO2-induced neutrophil and macrophage recruitment, proteoglycan degradation, oxidative stress, cytokine production (TNF-α, IL-1β, IL-6, and IL-10), COX-2 mRNA expression, and bone resorption as well as activation of Nrf2/HO-1 signaling pathway. These results demonstrate the potential therapeutic applicability of the dietary flavonoid quercetin to reduce pain and inflammatory damages associated with prosthesis wear process-induced arthritis.

Introduction

Chronic joint inflammation leads to morphological alterations characterized by destruction of the weight-bearing surfaces of joints. This clinical picture leads to partial or total replacement of the destroyed tissues surfaces, a procedure recognized as arthroplasty [1]. Clinical conditions leading to arthroplasty include osteoarthritis, inflammatory arthritis (such as rheumatoid arthritis), osteonecrosis, joint dysplasia, post-traumatic arthritis and tumors [2]. Furthermore, drug treatment can also lead to the emergency of arthroplasty. For instance, prolonged use of steroids leads to profound deleterious effects in hypothalamic–pituitary–adrenal axis function and also in bone, leading to osteoporosis, fractures and femur head necrosis, thus, requiring arthroplasty [3]. In this sense, arthroplasty procedure comprises an important and successfully conduit to arthritic pain relief, restoring mobility and improving the quality of life of patients. However, this process may fail as a result of infections or aseptic loosening due to osteolysis in the peri-prosthetic tissues [1], [2]. In fact, the incidence of osteolysis may reach up to 40% of the patients that underwent arthroplasty [1].

Frequently used materials in the replacements include polymethylmethacrylate, polyethylene, cobalt-chromium alloys and titanium [1], [4]. The release of prosthesis debris particles as a consequence of the wear process is a constant concern. These particles induce immune responses leading to activation of resident cells such as macrophages, and consequently phagocytosis of the wear debris [5]. The activated cells produce increasing amounts of chemical mediators such as receptor activator of nuclear factor kappa B ligand (RANKL), pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6 as well as reactive oxygen species leading to NFκB activation, perpetuating the aseptic inflammatory response in the peri-prosthetic tissues [1], [4], [6]. Moreover, the pro-inflammatory milieu induces osteoclastogenesis and more pronounced activation of osteoclasts contributing to the bone resorption and consequently increasing osteolytic process [1], [4]. As a result of this overall immune activation, there is rejection of the prosthesis and need of a novel surgery, which may not be possible depending on the health condition and age of the patient.

Titanium dioxide (TiO2), a white and odorless powder, besides being used in the production of orthopedic prosthesis, can be used as white pigment in paint, food colorant, sunscreens and cosmetic creams [7]. Titanium accumulation in human tissues such as lung, skin or synovia is characterized by a black pigment deposition, accompanied by fibrosis, necrosis or granulomatous reactions [8]. TiO2 is genotoxic and may penetrate the skin inducing oxidative damage of DNA [9], or remain trapped in tissues and organs promoting varying degrees of tissue damage [10], [11]. Moreover, TiO2 induces bronchoalveolar inflammatory response, affects varied organs and influences the magnitude of inflammatory response generated in the respiratory tract [12], [13]. Further supporting the clinical relevance of TiO2-induced arthritis, a patient with no family history of arthritis developed titanium-vanadium alloy implant-related arthritis [14].

The flavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a phenolic compound present in varied foods and plant-derived beverages of human diet such as apple, berries, grape, citrus, cocoa, onion, hot peppers, broccoli, green leafy vegetables, red wine and tea [15], [16], [17], [18]. Quercetin absorption occurs in the gastrointestinal tract and phase II enzymes processes this flavonoid in both stomach and intestines, whereas the resultant metabolites are processed further in the liver and kidney [18]. Biological activities described for quercetin include cardio and bowel protective functions, anti-inflammatory, analgesic, anticarcinogenic, antiulcer and antihypertensive effects [15], [16], [17]. Most of the quercetin effects were attributed to its antioxidant activities [17], [18], [19], [20]. However, it is not known whether quercetin treatment would be a conceivable approach to inhibit prosthesis-related joint inflammation.

In the present study, we evaluated the therapeutic effect of intraperitoneal (i.p.) quercetin in the pathogenesis of TiO2-induced arthritis in mice as well as its mechanisms.

Section snippets

General experimental procedures

In the first series of experiments, mice (n=6 per group per experiment) were submitted to a dose–response experiment and received intra-articular (i.a.) injection of 0.1, 0.3, 1 and 3 mg of TiO2 (suspended in saline solution 0.9%) per knee joint, for the evaluation of mechanical hyperalgesia and edema at the time of 1, 3, 5, 7 and 24 h in the first day, and subsequently, once a day from the 2nd to the 30th days. Immediately after the measurements at the 30th day, mice were anesthetized and

Intra-articular administration of TiO2 induces chronic articular mechanical hyperalgesia, edema and histopathological alterations in a dose-dependent manner

It has been demonstrated that the injection of TiO2 in the peritoneum, airpouch and knee joint (i.a.) induces inflammation, oxidative stress and cytokine production mimicking prosthesis inflammation [10], [11], [30]. Thus, the inflammatory response caused by prosthesis can be studied by injecting TiO2. In the first series of experiments, the hyperalgesic and pro-inflammatory properties of TiO2 along with histopathology were assessed (Fig. 1). Mice received intra-articular (i.a.) injection of

Discussion

Arthroplasty recovers joint mobility and functional independence of the patient. However, aseptic loosening induced by components of the prosthetic joint is a common event that accounts to the need of a novel surgery and prosthesis replacement [1], [2]. TiO2 is one of the most common components used in the manufacture of orthopedic prosthesis. Nevertheless, the prosthesis wear releases TiO2 that induces inflammation [1], [8], [9], [10], [11], [12], [30]. Quercetin is a flavonoid of our diet

Acknowledgements

This work was supported by grants from Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), São Paulo Research Foundation under grant agreements 2010/15014-9 and 2015/09034-0, Financiadora de Estudos e Projetos-Apoio à Infraestrutura (FINEP CT-INFRA), Ministério da Ciência, Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Ensino Superior (SETI), Departamento de Ciência e Tecnologia – Ministério da Saúde (DECIT/MS), Conselho Nacional de Desenvolvimento

Author contributions

S.M.B., S.S.M., D.L.P., J.P.M.I., R.C. and W.A.V.J. designed the study, planned experiments and analyze the data. S.M.B., S.S.M., F.A.P.-R., V.F., J.C., D.L.P., J.P.M.I. and S.Y.F performed the experiments. J.T.C.-N. and M.H.N. provided essential materials. S.M.B., S.S.M., R.C. and W.A.V.J. wrote the manuscript. W.A.V.J. supervised the study. All authors read and approved the manuscript.

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