[Show abstract][Hide abstract] ABSTRACT: Introduction:
Mesenchymal stem cells (MSCs) can protect bone marrow transplantation (BMT) recipients from the lethal acute graft-versus-host disease (aGVHD) development. However, the mechanisms underlying the anti-inflammatory properties of MSCs in aGVHD remain to be elucidated. The immunoregulatory properties of MSCs are mediated by their production of anti-inflammatory molecules, including IL-10 and TGF-β. On the other hand, MSCs can also produce proinflammatory cytokines during their normal growth, such as IL-1β and IL-6. These opposite actions may limit their therapeutic application in aGVHD. Therefore, optimization of the functional properties of MSCs can increase their benefits.
The expressions of mRNA and protein were analyzed by real-time PCR and western blotting, respectively. Expression of MSC markers was assessed by flow cytometry. An animal model of aGVHD was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. The recipient mice were divided into the control group and the therapy [adipose tissue-derived human MSCs (Ad-hMSCs) or rapamycin-treated Ad-hMSCs] groups. The survival, body weight and clinical score of aGVHD in transplanted mice were monitored.
Rapamycin pre-treatment of Ad-hMSCs increased mRNA synthesis of IL-10, indoleamine 2,3-dioxygenase, and TGF-β compared with untreated Ad-hMSCs. Rapamycin-treated Ad-hMSCs suppressed clonal expansion of interleukin-17-producing CD4(+) T (Th17) cells more effectively than untreated cells. mRNA expression of autophagy markers such as ATG5, LC3A and LC3B was significantly increased in the rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. Transmission electron microscopy revealed that Ad-hMSCs exposure to rapamycin resulted in the appearance of autophagic vacuoles. Interestingly, in vitro migration efficiency of rapamycin-treated Ad-hMSCs toward the CD4(+) T cells was increased significantly compared with the untreated cells. And, these effects were associated with autophagy induction capacity of rapamycin. In vivo, the inhibiting properties of MSCs on the clinical severities of aGVHD were greater in the mice receiving rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. The beneficial effects of rapamycin treatment in Ad-hMSCs shown in vivo were associated with a reduction of Th17 cells and an increase in regulatory T cells.
Rapamycin can optimize the immunomodulatory potential of Ad-hMSCs, suggesting a promising strategy of MSC use in aGVHD treatment.
Preview · Article · Oct 2015 · Stem Cell Research & Therapy
[Show abstract][Hide abstract] ABSTRACT: Increases in oxidative stress are thought to be associated with the development of osteoarthritis (OA). Eupatilin, one of the major compounds present in artemisia species, was shown to have both anti-oxidative and anti-inflammatory properties. Here, we investigated the in vivo effects of eupatilin on pain severity and cartilage degradation in an experimental rat model of OA, along with the mechanisms of action underlying these effects. Experimental OA was induced via an intra-articular injection of monosodium iodoacetate (MIA), with oral administration of eupatilin initiated on the day of MIA injection. Pain was assessed by measuring the paw withdrawal latency and threshold. Cartilage destruction was analyzed macroscopically and histomorphologically. The effects of eupatilin on mRNA expression were investigated in interleukin-1β (IL-1β)-stimulated human OA chondrocytes. Eupatilin treatment exhibited clear antinociceptive effects, along with an attenuation of cartilage degradation in OA rats. Additionally, the number of osteoclasts present in the subchondral bone region was significantly decreased following eupatilin treatment. Eupatilin reduced the expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), nitrotyrosine and inducible nitric oxide synthase (iNOS) in cartilage. mRNA levels of matrix metalloproteinase-3 (MMP-3), MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) were reduced in IL-1β-stimulated human OA chondrocytes, while tissue inhibitor of metalloproteinases-1 (TIMP-1) was induced. Phosphorylated protein levels of the c-jun N-terminal kinase (JNK) was reduced by eupatilin. Taken together, these results suggest that eupatilin suppresses oxidative damage and reciprocally enhances extracellular matrix production in articular chondrocytes, making eupatilin a promising therapeutic option for the treatment of OA.
[Show abstract][Hide abstract] ABSTRACT: Systemic vasculitis is a rare disease, and the diagnosis is very difficult when patient shows atypical symptoms. We experienced an unusual case of dysphagia caused by Churg-Strauss syndrome with lower cranial nerve involvement. A 74-year-old man, with a past history of sinusitis, asthma, and hearing deficiency, was admitted to our department for evaluation of dysphagia. He also complained of recurrent bleeding of nasal cavities and esophagus. Brain magnetic resonance imaging did not show definite abnormality, and electrophysiologic findings were suggestive of mononeuritis multiplex. Dysphagia had not improved after conventional therapy. Biopsy of the nasal cavity showed extravascular eosinophilic infiltration. All these findings suggested a rare form of Churg-Strauss syndrome involving multiple lower cranial nerves. Dysphagia improved after steroid therapy.
Full-text · Article · Jun 2015 · Annals of Rehabilitation Medicine
[Show abstract][Hide abstract] ABSTRACT: Acute graft-versus-host disease (aGVHD) is a major cause of mortality in allogeneic bone marrow transplantation. Here, the diminishing effect of activator protein-1 (AP-1) blocking with a synthetic retinoid (SR11302) on the severity of aGVHD in a murine model was investigated. MHC-mismatched strain combinations were used in vivo: C57BL/6 (H-2k(b)) donors into lethally irradiated BALB/c (H-2k(d)) recipients. SR11302 inhibited alloreactive T cell response in a dose-dependent manner and negatively regulated STAT3 activation. AP-1 blocking in T cells inhibited the differentiation of Th1 and Th17. Conversely, Foxp3(+) regulatory T cells (Treg) population dramatically expanded. Transfer of SR11302-treated donor splenocytes into lethally irradiated recipients diminished the lethality and clinical severity of aGVHD. In line with these results, AP-1 blocking in donor splenocytes exhibited reduced Th17/Th1 population and enhanced in vivo Treg population. Beneficial Treg expanding property of SR11302 was associated with the induction of Foxp3 and STAT5 transcription factor where the inhibiting property of Th17 was achieved by suppressing the phosphorylated form of STAT3 and enhancing SOCS3. Conclusively, the preventive potential of AP-1 inhibitor in aGVHD may be accomplished by altering CD4(+) T cell differentiation through modulating transcription factors.
Preview · Article · May 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Graft-versus-host disease (GVHD) caused by transplanted donor T cells remains the major obstacle of allogeneic bone marrow transplantation (BMT). Previous reports have suggested that IL-17-producing helper T (Th17) cells mediate the development of acute GVHD (aGVHD). Protein inhibitor of activated STAT3 (PIAS) inhibits the activity of the transcription factor STAT3, which is a pivotal transcription factor for Th17 differentiation. To elucidate whether PIAS3 could inhibit the development of aGVHD, pcDNA-PIAS3 or mock vector was administered in a murine model of aGVHD by intramuscular injection and subsequent electroporation. The results demonstrated that PIAS3 overexpression by pcDNA-vector administration significantly attenuated the clinical severity and histopathological severities of aGHVD involving the skin, liver, intestine, and lung. Additionally, the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression. Furthermore, phosphorylated (p) STAT3 activity in the spleen was profoundly attenuated in PIAS3-overexpressing GVHD mice. Interestingly, flow cytometric analysis demonstrated that the populations of CD21(high)CD23(low) marginal zone B cells were dramatically expanded in PIAS3-overexpressing mice. PIAS3-induced inhibition of aGVHD was largely related to the downregulation of Th1 and Th17 and the upregulation of Th2 and Treg populations. Both populations of pSTAT3(Tyr705)-expressing Th17 cells and B cells were significantly reduced in the spleens of PIAS3-overexpressing mice, whereas pSTAT5 activity was increased. In addition to CD4(+)CD25(+)Foxp3(+) Treg cells, the populations of CD8(+)CD25(+)Foxp3(+) Treg cells were also expanded by treatment with PIAS3. These data suggest the therapeutic potential of PIAS3 in the development of aGVHD through reciprocal regulation of Th17/Treg lineages.
No preview · Article · Apr 2014 · Immunology letters
[Show abstract][Hide abstract] ABSTRACT: Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA.
Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti-type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17-producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry.
Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen-specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor-related orphan nuclear receptor γt and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice.
The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway.
No preview · Article · Apr 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage. And, increased oxidative stress plays a relevant role in the pathogenesis of OA. Ursodeoxycholic acid (UDCA) is a used drug for liver diseases known for its free radical-scavenging property. The objectives of this study were to investigate the in vivo effects of UDCA on pain severity and cartilage degeneration using an experimental OA model and to explore its mode of actions. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration UDCA was initiated on the day of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1β (IL-1β), IL-6, nitrotyrosine and inducible nitric oxide synthase (iNOS) in knee joints. UDCA showed an antinociceptive property and attenuated cartilage degeneration. OA rats given oral UDCA significantly exhibited a decreased number of osteoclasts in subchondral bone legion compared with the vehicle-treated OA group. UDCA reduced the expression of IL-1β, IL-6, nitrotyrosine and iNOS in articular cartilage. UDCA treatment significantly attenuated the mRNA expression of matrix metalloproteinase-3 (MMP-3), -13, and ADAMTS5 in IL-1β-stimulated human OA chondrocytes. These results show the inhibitory effects of UDCA on pain production and cartilage degeneration in experimentally induced OA. The chondroprotective properties of UDCA were achieved by suppressing oxidative damage and inhibiting catabolic factors that are implicated in the pathogenesis of cartilage damage in OA.
[Show abstract][Hide abstract] ABSTRACT: Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727). On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation - suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4(+)CD25(+)Foxp3(+) Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4(+) T cells, and the effect was associated with retinoic acid-related orphan receptor γT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4(+) (cytotoxic T-lymphocyte antigen 4), PD-1(+) (programmed cell death protein 1) and GITR(+) (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4(+) cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.
[Show abstract][Hide abstract] ABSTRACT: Interleukin 34 (IL-34) is a recently discovered cytokine that binds macrophage colony-stimulating factor (M-CSF) receptor. Rheumatoid arthritis (RA) is characterized by increased osteoclastogenesis. To identify the significance of IL-34 in RA, the IL-34 concentration was measured in serum and synovial fluid (SF).
IL-34 concentrations were measured in serum from patients with RA (n = 113), patients with osteoarthritis (OA; n = 56), and controls (n = 36), and in SF isolated from patients with RA (n = 36) or OA (n = 24). Correlations between serum IL-34 levels and clinical features in RA were assessed. The levels of IL-1β, IL-6, IL-17α, interferon-γ-induced protein 10, receptor activator of nuclear factor κB ligand (RANKL), and Dickkopf-1 were also measured.
Patients with RA had a higher mean serum level of IL-34 than did patients with OA and controls (188.0 ± 550.3, 36.6 ± 38.0, and 49.1 ± 78.5 pg/ml, respectively). Similarly, SF IL-34 concentration was higher in patients with RA than in those with OA. IL-34 levels were positively associated with IL-6 levels in serum from patients with RA and OA. SF IL-34 concentration correlated significantly with IL-6 and RANKL levels only in RA. The serum level of IL-34 was not correlated with systemic osteoporosis and radiographic joint damage in RA. IL-34 levels in the serum from patients with RA were positively correlated with rheumatoid factor and anticyclic citrullinated peptide antibody titers (r = 0.282 and 0.491, respectively).
Circulating IL-34 levels in RA correlated with autoantibody production. Further investigations of localized and systemic effects of IL-34 are warranted to elucidate RA pathogenesis.
No preview · Article · Sep 2013 · The Journal of Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Baker cyst is an enlargement of the gastrocnemius-semimembranosus bursa. Neuropathy can occur due to either direct compression from the cyst itself or indirectly after cyst rupture. We report a unique case of a 49-year-old man with left sole pain and paresthesia who was diagnosed with posterior tibial neuropathy at the lower calf area, which was found to be caused by a ruptured Baker cyst. The patient's symptoms resembled those of lumbosacral radiculopathy and tarsal tunnel syndrome. Posterior tibial neuropathy from direct pressure of ruptured Baker cyst at the calf level has not been previously reported. Ruptured Baker cyst with resultant compression of the posterior tibial nerve at the lower leg should be included in the differential diagnosis of patients who complain of calf and sole pain. Electrodiagnostic examination and imaging studies such as ultrasonography or magnetic resonance imaging should be considered in the differential diagnosis of isolated paresthesia of the lower leg.
Full-text · Article · Aug 2013 · Annals of Rehabilitation Medicine
[Show abstract][Hide abstract] ABSTRACT: In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model.
Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4(+) splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4(+)Foxp3(+) splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4(+) regulatory T cells (Tregs) as well as CD8(+) Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations.
In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4(+) and CD8(+) Treg) cell lineages as well as B cell homeostasis.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To determine whether the frequencies of specific killer cell immunoglobulin-like receptors (KIR) genotypes are associated with the incidence of uveitis in ankylosing spondylitis (AS) and Behçet disease (BD).
The authors analyzed the frequency of 16 KIR genes in Koreans with either AS (110 patients, all HLA-B27-positive) or BD (86 patients), using polymerase chain reaction sequence-specific oligonucleotide probing.
The frequency of the inhibitory receptor KIR3DL1 was lower in AS patients affected by uveitis than that in the general population (p < 0.05). The frequency of the KIR3DL1(-)/2DS3(-) was significantly higher in AS patients with uveitis (odds ratio = 9.306, p = 0.007).
The study suggests that KIR3DL1 might associate with the resistance to AS-associated uveitis by influencing natural killer cell activity.
No preview · Article · Apr 2013 · Ocular immunology and inflammation
[Show abstract][Hide abstract] ABSTRACT: Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The 'early' effect of each cytokine was investigated at the time of first RANKL treatment, whereas the 'late' effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.
Preview · Article · Apr 2013 · International Journal of Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (ĸ = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration ≤ 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.
Preview · Article · Feb 2013 · Journal of Korean medical science
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage and chronic pain. Although cyclooxygenase-2 (COX-2) inhibitors such as celecoxib are recommended to patients at high risk of gastrointestinal (GI) adverse events, COX-2 inhibitors do not completely prevent GI adverse events. Rebamipide, a gastroprotective agent, has anti-inflammatory properties and acts as an oxygen radical scavenger. The aim of this study was to investigate the in vivo effects of coadministration of rebamipide and celecoxib in an OA rat model. OA was induced by intra-articular injection of monosodium iodoacetate. Oral administration of rebamipide was initiated on the day of OA induction. In this study, rebamipide showed antinociceptive properties and attenuated cartilage degeneration. Rebamipide reduced the expression of matrix metalloproteinase 13, interleukin-1β, inducible nitric oxide synthase, and nitrotyrosine in OA cartilage. OA rats treated with celecoxib in combination with rebamipide demonstrated a higher pain threshold than those treated with monotherapy. Histological examination also showed that the joints from OA animals treated with combination therapy demonstrated less cartilage damage than those of animals treated with monotherapy. We showed that the potential benefit of combination therapy with celecoxib and rebamipide on pain and cartilage degeneration in OA.
No preview · Article · Jan 2013 · Archives of Pharmacal Research