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Brief communication |
Address correspondence to Dr. Saliha Karatay, Atatürk Üniversitesi, Tip Fakültesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dali, 25240 Erzurum, Turkey; tel 90 442 236 1212/ 1625; fax 90 442 236 1301; e-mail: skaratay73{at}hotmail.com.
Abstract
The aim of this study was to evaluate the effects of different hyaluronic acid (HA) forms on synovial fluid levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the treatment of patients with knee osteoarthritis (OA). Forty patients were randomly assigned to 2 groups that were treated with native sodium hyaluronate (group I) or cross-linked hylan G-F 20 (group II). Clinical evaluations and synovial fluid aspirations were performed before the 1st injection (baseline), the 2nd injection (week 1), the 3rd injection (week 2), and at 1 week after the 3rd injection (week 3). Synovial fluid levels of both ICAM-1 and VCAM-1 were significantly reduced at weeks 1 to 3, compared to the baseline values. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index was used for clinical evaluations; the WOMAC pain score and physical function score were progressively improved at weeks 1 to 3 in both groups; the WOMAC stiffness score was significantly improved at week 3 in both groups. No significant differences were noted between the 2 treatment groups in respect to ICAM-1 levels, VCAM-1 levels, WOMAC pain score, stiffness score, or physical function score at any time. The decreased ICAM-1 and VCAM-1 levels after intra-articular HA injection may help to explain the anti-inflammatory effects of HA therapy in knee OA.
(received 1 April 2004; accepted 1 May 2004)
Keywords: hyaluronic acid, molecular weight, ICAM-1, VCAM-1, knee osteoarthritis, synovial fluid
Introduction
Osteoarthritis (OA), the most common joint disease in the world, is often thought to result from wear and tear on a joint. Although the incidence of OA increases with age, a specific causative agent of OA has not been identified. However, it is believed that the disease process is a consequence of mechanical and biological factors that affect the balance between degradation and repair in articular tissues. Although these processes occur mainly on the articular cartilage, the entire joint structure, including subchondral bone, synovial membrane, joint capsule, and ligaments, is affected in OA [1]. Biomechanical stress causes various structural and biochemical changes that result in the production of proinflammatory cytokines and activate an inflammatory chemical reaction cascade in articular tissues. Chondrocytes of OA patients actively produce prostaglandins, tumor necrosis factor-
(TNF-), interleukin-1ß (IL-1ß), IL-6, and IL-8 [2]. Recent studies demonstrate inflammatory changes in the synovial membrane of OA patients, including synovial hypertrophy and infiltration of the underlying tissue by various inflammatory cells [3,4]. Leukocytes play a pivotal role in inflammation because of their antimicrobial, secretory, and phagocytic activities [5]. A primary feature of the inflammatory response is the recruitment of leukocytes from the vessel wall into inflamed tissue and their interaction with other cell types, such as macrophages and fibroblasts [5,6]. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) play important roles in endothelial-leukocyte interactions [5]. Their regulated expression affects the binding and transmigration of leukocytes during inflammation [6].
Intra-articular injections of hyaluronic acid (HA) have been used to treat knee OA, in order to minimize mechanical stress within the joint. The average molecular weight of HA products varies, depending on the manufacturer. Native sodium hyaluronate (eg, Orthovisc®, 1–3 million Da mol wt) [7] and cross-linked hylan G-F 20 (eg, Synvisc®, 6 million Da) [8] are currently being used to treat human OA. There are various reports about the effects of different HA products in knee OA [9,10]. Studies have shown that HA treatment aleviates the OA symptoms, such as pain, stiffness, and functional impairment, normalizes the properties of synovial fluid, suppresses cartilage degeneration, and protects the surface of joints [11,12]. Exogenous HA affects various inflammatory mediators and leukocyte functions [13]. However, the effects of HA on soluble endothelial adhesion molecules that influence inflammatory status have not yet been elucidated. Therefore, we investigated the effects of 2 different HA products on synovial fluid levels of ICAM-1 and VCAM-1 in patients with OA.
Material and Methods
Subjects. Forty patients with knee OA that fulfilled the American College of Rheumatology criteria [14] were enrolled in this study. All patients had radiographic changes of knee OA equal to Kellgren-Lawrence [15] grade II or III. None of the patients used analgesic or non-steroidal anti-inflammatory drugs. Patients with concomitant rheumatological disease, active synovitis, surgical or arthroscopic interventions, or intra-articular steroid or HA treatment during the past 6 months were excluded.
The patients were randomly assigned to 2 groups that were treated with native sodium hyaluronate (Orthovisc®, Anika Therapeutics, 2 ml, 30 mg) or cross-linked hylan G-F 20 (Synvisc®, Wyeth, 2 ml, 16 mg). Intra-articular sodium hyaluronate and cross-linked hylan G-F 20 injections were administered once each week for 3 weeks to patients in group I and group II.
Clinical evaluation and synovial fluid aspiration were performed before the 1st injection (baseline), the 2nd injection (week 1), the 3rd injection (week 2), and at one week after the 3rd injection (week 3). For the clinical examination, we used the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [16], which assesses the levels of pain, stiffness, and functional impairment in knee OA. The WOMAC pain scores (0–20), stiffness scores (0–8), and physical function scores (0–68) were calculated separately.
Biochemical measurements. Synovial fluid samples were aspirated from the knee joints and stored at –80°C in Eppendorf tubes. Commercial ELISA kits were used to assay sICAM-1 (Catalog #KHS-5412, BioSource Int.) and sVCAM-1 (Catalog #KHT-0602, BioSource Int.) in the synovial fluid samples.
Statistics. Statistical analyses was performed by the SPSS 10.0 program for Windows. Paired t-tests were used to compare data within groups at baseline, week 1, week 2 and week 3. Non-paired t-tests were used to compare data between the groups. Correlations between ICAM-1 and VCAM-1 levels were tested by Pearson’s correlation coefficient. Values with p <0.05 were deemed statistically significant.
Results
The patients in group I (7 men, 13 women) had an average age of 62 yr (range 57–75). Patients in group II (5 men, 15 women), had an average age of 61 yr (range 55–75). At baseline, no differences of demographic features, clinical indices, or laboratory values were observed between the 2 groups (p >0.05).
Synovial fluid ICAM-1 levels were significantly reduced at weeks 1, 2, and 3 in both groups (Fig. 1
). Synovial fluid VCAM-1 levels were also significantly reduced at weeks 1, 2, and 3 in both groups (Fig. 2). No significant correlations were recorded between ICAM-1 and VCAM-1 levels in the 2 groups (p >0.05).
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). No significant differences were noted between the 2 treatment groups in respect to synovial fluid levels of ICAM-1 or VCAM-1, or the WOMAC pain scores, stiffness scores, or physical function scores at any time during the study.
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Pharmaceutical HA preparations with various molecular weights are available for OA treatment, but the influence of their molecular weights on therapeutic efficacy has not been clearly established. Studies indicated that high molecular weight HA products were more biologically active in human OA, compared to HA products with lower molecular weights [17]. On the contrary, studies of OA in large animals indicated that the low molecular weight HA preparations were more effective than high molecular weight products in decreasing synovial inflammation, improving the properties of synovial fluid, and suppressing cartilage damage [9,18]. In the present study, we used 2 different HA products (ie, sodium hyaluronate and hylan G-F 20). We observed that WOMAC pain and physical function scores were progressively improved by administration of either HA product; there were no significant differences between the effects of the 2 products. In other studies of patients with knee OA, efficacy of these products for pain relief and aleviation of functional impairment has also been noted [7–9].
Although the precise molecular mechanism of HA’s action is unclear, increasing the viscoelasticity of synovial fluid seems to play an important role. During the development of OA, the molecular weight and concentration of synovial fluid HA decrease [19]. Loss of synovial fluid viscoelasticity reduces the lubrication and protection of the joint tissues and enhances their susceptibility to cartilage damage by wear and tear. This mechanism plays a central role in pain production and the inflammatory response in OA [20]. The increasing viscoelasticity of synovial fluid with exogenous HA may restrict the recruitment of macrophage and leukocyte subtypes and the expression of proinflammatory cytokines, preventing cartilage destruction and reducing the release of cartilage breakdown products. In addition, studies showed that pain was aleviated by intra-articular HA treatment, with reduced production of bradykinin, prostaglandin E2, and substance P, as well as direct inhibition of nociceptive afferents [21,22].
The injected HA products remain within the joint space for hours to days, but their clinical efficacy often continues for months [19,23]. The anti-inflammatory and anti-nociceptive properties of HA may possibly explain the long-term effects. However, numerous anti-inflammatory actions of HA have been reported. In vitro studies showed that exogenous HA inhibits arachidonic acid release and IL-1-induced prostaglandin E2 production by human osteoarthritic synoviocytes [24,25]. Protective effects of HA against IL-1, oxygen free radicals, and certain proteinases have been reported [26]. Moreover, exogenous HA suppresses angiogenesis [27].
In searching the literature, we did not find any study of the effect of HA treatment on endothelial adhesion molecule levels in synovial fluid. In this study, we show that synovial fluid ICAM-1 and VCAM-1 levels are decreased by HA treatments in patients with knee OA. HA injections may directly or indirectly diminish the ICAM-1 and VCAM-1 expression in articular tissues. Various proinflammatory cytokines, eg, TNF-, IL-1 and interferon-
(IFN-), increase the expression of endothelial adhesion molecules [6]. HA injections may stimulate endogenous production of additional hyaluronate by human synoviocytes and may normalize the properties of synovial fluid [28]. Concurrently, the synovial fluid concentrations of substances that stimulate ICAM-1 and VCAM-1 production may decrease, resulting indirectly in diminished expression of ICAM-1 and VCAM-1. Suppression of ICAM-1 and VCAM-1 synthesis may decrease the inflammatory response by preventing selective adhesion and transmigration of leukocyte subtypes into inflammation sites.
Specific anti-adhesion therapy for endothelial adhesion molecules leads to partial inhibition of leukocyte recruitment in collagen-induced and adjuvant-induced arthritis [29,30]. The presence of synovial inflammation in OA is considered a secondary phenomenon that is related to the destruction of cartilage and the release of cartilage breakdown products in synovial fluid [2]. Therefore, suppression of inflammation may retard the progression and severity of knee OA. Pain is a major symptom of the inflammatory response, and the decreased ICAM-1 and VCAM-1 levels in synovial fluid may contribute to the beneficial effects of HA on joint pain.
In conclusion, intra-articular HA treatment is effective in reducing pain perception, aleviating functional impairment, and decreasing synovial fluid ICAM-1 and VCAM-1 levels in patients with knee OA. These effects are not influenced by the different molecular weights and chemical structures of the 2 HA preparations that were tested in this study. By reducing the levels of ICAM-1 and VCAM-1 in synovial fluid, intra-articular HA injections may help to suppress the inflammatory response in knee OA.
References
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