Intraarticular Injection (intraarticular + injection)

Distribution by Scientific Domains

Selected Abstracts

Intraarticular Injection and Closed Glenohumeral Reduction with Emergency Ultrasound

Michael B. Stone MD
No abstract is available for this article. [source]

Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

Sadaf Ashraf
Objective To determine whether blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence and whether inhibiting this angiogenesis at the onset of persistent inflammation leads to its subsequent resolution. Methods Inflammation and angiogenesis were induced by injection of 0.03% carrageenan and/or 6 pmoles of fibroblast growth factor 2 (FGF-2) into rat knees. A brief treatment with the angiogenesis inhibitor PPI-2458 (5 mg/kg orally on alternate days) was administered 1 day before and up to 3 days after synovitis induction. Controls comprised naive and vehicle-treated rats. Synovial angiogenesis was measured using the endothelial cell proliferation index, and inflammation was determined by measuring joint swelling and macrophage percentage area. Data are presented as the geometric mean (95% confidence interval). Results Intraarticular injection of 0.03% carrageenan into rat knees produced acute synovitis, which was not associated with synovial angiogenesis and which resolved within 29 days. Injection of FGF-2 (6 pmoles) induced synovial angiogenesis without significant synovitis. Stimulation of angiogenesis with FGF-2 at the time of carrageenan injection was followed by synovitis that persisted for 29 days. Persistence of carrageenan/FGF-2,induced synovitis was prevented by systemic administration of 3 doses of the angiogenesis inhibitor PPI-2458 during the acute phase. Conclusion Our findings indicate that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis, and brief antiangiogenic treatment during the acute phase of synovitis may prevent its subsequent progression. Clinical studies will be needed to determine whether brief antiangiogenic treatment may reduce the burden of inflammatory joint diseases such as rheumatoid arthritis by facilitating the resolution of early synovitis. [source]

N -acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis

Shuji Nakagawa
Abstract We investigated whether N -acetylcysteine (NAC), a precursor of glutathione, could protect rabbit articular chondrocytes against nitric oxide (NO)-induced apoptosis and could prevent cartilage destruction in an experimental model of osteoarthritis (OA) in rats. Isolated chondrocytes were treated with various concentrations of NAC (0,2 mM). Apoptosis was induced by 0.75 mM sodium nitroprusside (SNP) dehydrate, which produces NO. Cell viability was assessed by MTT assay, while apoptosis was evaluated by Hoechst 33342 and TUNEL staining. Intracellular reactive oxygen species (ROS) and glutathione levels were measured, and expression of p53 and caspase-3 were determined by Western blotting. To determine whether intraarticular injection of NAC prevents cartilage destruction in vivo, cartilage samples of an OA model were subjected to H&E, Safranin O, and TUNEL staining. NAC prevented NO-induced apoptosis, ROS overproduction, p53 up-regulation, and caspase-3 activation. The protective effects of NAC were significantly blocked by buthionine sulfoximine, a glutathione synthetase inhibitor, indicating that the apoptosis-preventing activity of NAC was mediated by glutathione. Using a rat model of experimentally induced OA, we found that NAC also significantly prevented cartilage destruction and chondrocyte apoptosis in vivo. These results indicate that NAC inhibits NO-induced apoptosis of chondrocytes through glutathione in vitro, and inhibits chondrocyte apoptosis and articular cartilage degeneration in vivo. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:156,163, 2010 [source]

The effect of hyaluronic acid on IL-1,-induced chondrocyte apoptosis in a rat model of osteoarthritis

Pang-Hu Zhou
Abstract The purpose of this article was to study the effect of hyaluronic acid (HA) on chondrocyte apoptosis in a rat osteoarthritis in vitro model (exposure to IL-1,) and explore its mechanism. A rat in vitro model of osteoarthritis (OA) was established using 10 ng/mL IL-1, as a modulating and chondrocyte apoptosis inducing agent. Different doses of HA (10, 20, and 40 µg/mL) were added 1 h prior to the addition of IL-1, to a monolayer culture of freshly isolated juvenile rat chondrocytes. The ratio of apoptotic cell death was surveyed by Annexin V-FITC and propidium iodide double-labeling FACS analysis. The mitochondrial membrane potential of chondrocytes was evaluated by rhodamine-123 fluorescence. The mitochondrial function was evaluated through detecting the ATP production by a luciferase assay. The reverse transcription polymerase chain reaction (RT-PCR) was performed to measure mRNA expression levels of inducible oxide synthase (iNOS). HA could inhibit IL-1,-induced chondrocyte apoptosis in our cell culture model system. It was showed that addition of HA to the medium was able in a dose-dependent way to reduce the impairment of the mitochondrial membrane potential and to restore mitochondrial ATP production. This study shows that HA could suppress in a dose-dependent way chondrocyte apoptosis in our IL-1,-induced osteoarthritis model. The suppression of inflammatory cytokine activity within the joint might be one important mechanism of the clinical action of intraarticular injection of HA in the treatment of OA. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source]

Does intraarticular morphine improve pain control with femoral nerve block after anterior cruciate ligament reconstruction? (Vanderbilt University Medical Center, Nashville, TN) American Journal of Sports Medicine 2001;29:327,332.

PAIN PRACTICE, Issue 4 2001
Eric C. McCarthy
In a prospective, randomized, double-blinded manner, the authors of this study compared the effects of a preoperative intraarticular injection of morphine (5 mg) or a placebo, combined with a postoperative femoral nerve block, on postoperative pain. Sixty-two patients underwent an arthroscopically assisted anterior cruciate ligament reconstruction using patellar tendon autograft under general anesthesia. No statistical difference between the 2 groups was evident in terms of age, sex, weight, operative time, volume of bupivacaine received with the femoral nerve block, or tourniquet use or tourniquet time. A comparison of the visual analog pain scale scores revealed no statistical difference between the groups at any point after the operation. Both groups had a significant decrease in visual analog scale scores after the femoral nerve block. No significant difference in postoperative narcotic medication use was evident in the recovery room or at home. A post hoc analysis revealed that the study power reached 87% with a significance level of 5%. Conclude that the postoperative femoral nerve block was effective and intraarticular morphine provided no additional benefit. Comment by Alan David Kaye, M.D., Ph.D., and Erin Bayer, M.D. This prospective, randomized, double blinded study compared the effects of preoperative intraarticular injection of morphine or a placebo along with postoperative femoral "three-in-one" block on postoperative pain. 62 patients underwent arthroscopic ACL reconstruction under general anesthesia. After induction of anesthesia, patients were injected with either morphine 5 mg or placebo along with local anesthetics intraarticularly. Femoral nerve blocks were performed in the recovery room with a total of 3 mg/kg bupivacaine. The VAS of pain was assessed immediately postoperatively and at six time points afterward up to 24 hours. This study concluded that there were no statistical differences between the two groups comparing VAS. Also no significant difference was observed in postoperative narcotic use in the recovery room or at home. The study included antiemetics; however, the results did not include if the morphine group had a larger incidence of nausea or vomiting postoperatively. Finally, the authors suggest that there are no advantages to use of intraarticular morphine with a femoral nerve block post-operatively. A future study employing preoperative femoral nerve block with or without use of intraarticular morphine might be interesting to see on arthroscopic ACL repairs to obtain adequate analgesia as the authors suggested. [source]

CTLA-4Ig blocks the development and progression of citrullinated fibrinogen,induced arthritis in DR4-transgenic mice

David Yue
Objective To assess the role of T cells in the mouse model of citrullinated human fibrinogen,induced rheumatoid arthritis (RA) using CTLA-4Ig, an agent that blocks T cell costimulation, which is required for T cell activation. Methods Humanized HLA,DR,1*0401,transgenic (DR4-Tg) mice were immunized with Cit,human fibrinogen to induce arthritis. Prior to, and at the onset or peak of, arthritis, the DR4-Tg mice were treated with CTLA-4Ig or control human IgG1 or were left untreated. Arthritis development and progression were monitored by measuring ankle swelling with calipers and by assessing histopathologic changes. The immune responses to the citrullinated antigens and the corresponding unmodified antigens, as well as the arthritogenicity of lymphocytes from these mice, were examined. The latter was performed using lymphocyte transfers from CTLA-4Ig,treated or control mice via intraperitoneal injection into naive DR4-Tg mice. Recipient mice also received an intraarticular injection of Cit,human fibrinogen, unmodified human fibrinogen, or vehicle. Results CTLA-4Ig,treated, but not human IgG1-treated, arthritic mice had significantly reduced ankle swelling and pathologic joint damage. Treatment with CTLA-4Ig, but not human IgG1, suppressed Cit,human fibrinogen,induced T cell activation, including citrulline-specific T cell activation, when given prior to disease onset. Transfer of splenic lymphocytes from untreated or human IgG1,treated arthritic mice caused arthritis in recipients, and this occurred when Cit,human fibrinogen, but not unmodified fibrinogen, was deposited into the joint. Splenocytes from CTLA-4Ig,treated mice were unable to transfer arthritis. Conclusion Activated citrulline-specific T cells play a direct role in the development and progression of arthritis in this model of Cit,human fibrinogen,induced RA. [source]

Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model

Hee-Jeong Im
Objective To verify the biologic links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA), and to investigate the molecular basis of alterations in nociceptive pathways caused by OA-induced pain. Methods An animal model of knee joint OA pain was generated by intraarticular injection of mono-iodoacetate (MIA) in Sprague-Dawley rats, and symptomatic pain behavior tests were performed. Relationships between development of OA with accompanying pain responses and gradual alterations in cellular and structural knee joint components (i.e., cartilage, synovium, meniscus, subchondral bone) were examined by histologic and immunohistologic analysis, microscopic examination, and microfocal computed tomography. Progressive changes in the dynamic interrelationships between peripheral knee joint tissue and central components of nociceptive pathways caused by OA-induced pain were examined by investigating cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord. Results We observed that structural changes in components of the peripheral knee joint correlate with alterations in the central compartments (dorsal root ganglia and the spinal cord) and symptomatic pain assessed by behavioral hyperalgesia. Our comparative gene expression studies revealed that the pain pathways in MIA-induced knee OA may overlap, at least in part, with neuropathic pain mechanisms. Similar results were also observed upon destabilization of the knee joint in the anterior cruciate ligament transection and destabilization of the medial meniscus models of OA. Conclusion Our results indicate that MIA-induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacologic studies on nociceptive pain pathways caused by OA, and provide key in vivo evidence that OA pain is caused by central sensitization through communication between peripheral OA nociceptors and the central sensory system. Furthermore, our data suggest a mechanistic overlap between OA-induced pain and neuropathic pain. [source]

A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis

Young-Sool Hah
Objective Nuclear factor-,B (NF-,B) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-,B, might have antiarthritic effects. Methods An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. Results In vitro experiments demonstrated that AdA20 suppressed NF-,B activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor , in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus,injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-,B signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-,B. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. Conclusion These results suggest that using A20 to block the NF-,B pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA. [source]

Nucleotide-binding oligomerization domain 2 and Toll-like receptor 2 function independently in a murine model of arthritis triggered by intraarticular peptidoglycan

Holly L. Rosenzweig
Objective Blau syndrome is an autoinflammatory disease resulting from mutations in the NOD2 gene, wherein granulomatous arthritis, uveitis, and dermatitis develop. The mechanisms by which aberrant NOD2 causes joint inflammation are poorly understood. Indeed, very few studies have addressed the function of nucleotide-binding oligomerization domain 2 (NOD-2) in the joint. This study was undertaken to investigate NOD-2 function in an experimental model of arthritis and to explore the potential interplay between Toll-like receptor 2 (TLR-2) and NOD-2 in joint inflammation. Methods Mice deficient in TLR-2, myeloid differentiation factor 88 (MyD88), or NOD-2 and their wild-type controls were given an intraarticular injection of muramyl dipeptide (MDP), peptidoglycan (PG; a metabolite of which is MDP), or palmitoyl-3-cysteine-serine-lysine-4 (Pam3CSK4), a synthetic TLR-2 agonist. Joint inflammation was assessed by near-infrared fluorescence imaging and histologic analysis. Results Locally administered PG resulted in joint inflammation, which was markedly reduced in mice deficient in either TLR-2 or the TLR signaling mediator MyD88. In addition to TLR-2 signaling events, NOD-2 mediated joint inflammation, as evidenced by the fact that mice deficient in NOD-2 showed significantly reduced PG-induced arthritis. TLR-2 or MyD88 deficiency did not influence arthritis induced by the specific NOD-2 agonist MDP. In addition, NOD-2 deficiency did not alter the TLR-2,dependent joint inflammation elicited by the synthetic TLR-2 agonist Pam3CSK4. Conclusion Whereas NOD-2 and TLR-2 are both critical for the development of PG-induced arthritis, they appear to elicit inflammation independently of each other. Our findings indicate that NOD-2 plays an inflammatory role in arthritis. [source]

Induction of apoptosis in the synovium of mice with autoantibody-mediated arthritis by the intraarticular injection of double-stranded MicroRNA-15a

Yoshihiko Nagata
Objective MicroRNA is a family of noncoding RNAs that exhibit tissue-specific or developmental stage,specific expression patterns and are associated with human diseases. MicroRNA-15a (miR-15a) is reported to induce cell apoptosis by negatively regulating the expression of Bcl-2, which suppresses the apoptotic processes. The purpose of this study was to investigate whether double-stranded miR-15a administered by intraarticular injection could be taken up by cells and could induce Bcl-2 dysfunction and cell apoptosis in the synovium of arthritic mice in vivo. Methods Autoantibody-mediated arthritis was induced in male DBA/1J mice. In the experimental group, double-stranded miR-15a labeled with FAM,atelocollagen complex was injected into the knee joint. In the control group, control small interfering RNA,atelocollagen complex was injected into the knee joint. Synovial expression of miR-15a was analyzed by quantitative polymerase chain reaction, FAM by fluorescence microscopy, Bcl-2 by Western blotting, and Bcl-2 and caspase 3 by immunohistochemistry. Results The expression of miR-15a in the synovium of the experimental group was significantly higher than that in the control group. Green fluorescence emission of FAM was observed in the synovium of the experimental group. Bcl-2 protein was down-regulated and the expression of caspase 3 was increased as compared with that in the control group. Conclusion These results indicate that the induction of cell apoptosis after intraarticular injection of double-stranded miR-15a occurs through inhibition of the translation of Bcl-2 protein in arthritic synovium. [source]

Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble flt-1

Tomoyuki Matsumoto
Objective The control of angiogenesis during chondrogenic differentiation is an important issue affecting the use of stem cells in cartilage repair, especially with regard to the persistence of regenerated cartilage. This study was undertaken to investigate the effect of vascular endothelial growth factor (VEGF) stimulation and the blocking of VEGF with its antagonist, soluble Flt-1 (sFlt-1), on the chondrogenesis of skeletal muscle-derived stem cells (MDSCs) in a rat model of osteoarthritis (OA). Methods We investigated the effect of VEGF on cartilage repair in an immunodeficiency rat model of OA after intraarticular injection of murine MDSCs expressing bone morphogenetic protein 4 (BMP-4) in combination with MDSCs expressing VEGF or sFlt-1. Results In vivo, a combination of sFlt-1, and BMP-4,transduced MDSCs demonstrated better repair without osteophyte formation macroscopically and histologically following OA induction, when compared with the other groups. Higher differentiation/proliferation and lower levels of chondrocyte apoptosis were also observed in sFlt-1, and BMP-4,transduced MDSCs compared with a combination of VEGF- and BMP-4,transduced MDSCs or with BMP-4,transduced MDSCs alone. In vitro experiments with mixed pellet coculture of MDSCs and OA chondrocytes revealed that BMP-4,transduced MDSCs produced the largest pellets, which had the highest gene expression of not only type II collagen and SOX9 but also type X collagen, suggesting formation of hypertrophic chondrocytes. Conclusion Our results demonstrate that MDSC-based therapy involving sFlt-1 and BMP-4 repairs articular cartilage in OA mainly by having a beneficial effect on chondrogenesis by the donor and host cells as well as by preventing angiogenesis, which eventually prevents cartilage resorption, resulting in persistent cartilage regeneration and repair. [source]

Triggering of proteinase-activated receptor 4 leads to joint pain and inflammation in mice

Jason J. McDougall
Objective To investigate the role of proteinase-activated receptor 4 (PAR-4) in mediating joint inflammation and pain in mice. Methods Knee joint blood flow, edema, and pain sensitivity (as induced by thermal and mechanical stimuli) were assessed in C57BL/6 mice following intraarticular injection of either the selective PAR-4 agonist AYPGKF-NH2 or the inactive control peptide YAPGKF-NH2. The mechanism of action of AYPGKF-NH2 was examined by pretreatment of each mouse with either the PAR-4 antagonist pepducin P4pal-10 or the bradykinin antagonist HOE 140. Finally, the role of PAR-4 in mediating joint inflammation was tested by pretreating mice with acutely inflamed knees with pepducin P4pal-10. Results PAR-4 activation caused a long-lasting increase in joint blood flow and edema formation, which was not seen following injection of the control peptide. The PAR-4,activating peptide was also found to be pronociceptive in the joint, where it enhanced sensitivity to a noxious thermal stimulus and caused mechanical allodynia and hyperalgesia. The proinflammatory and pronociceptive effects of AYPGKF-NH2 could be inhibited by pepducin P4pal-10 and HOE 140. Finally, pepducin P4pal-10 ameliorated the clinical and physiologic signs of acute joint inflammation. Conclusion This study demonstrates that local activation of PAR-4 leads to proinflammatory changes in the knee joint that are dependent on the kallikrein,kinin system. We also show for the first time that PARs are involved in the modulation of joint pain, with PAR-4 being pronociceptive in this tissue. Thus, blockade of articular PAR-4 may be a useful means of controlling joint inflammation and pain. [source]

Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin

Carl R. Flannery
Objective Lubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction-resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis-associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA). Methods Binding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage-lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell-binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis. Results LUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease-modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage. Conclusion Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities. [source]

Promotion of the local differentiation of murine Th17 cells by synovial macrophages during acute inflammatory arthritis

Paul J. Egan
Objective To examine the generation of proinflammatory Th17 cells at the site of tissue inflammation and in draining lymph nodes using an interleukin-17 (IL-17),dependent model of acute inflammatory arthritis. Methods Arthritis was elicited in mice by intraarticular injection of methylated bovine serum albumin (mBSA) into the knee and subcutaneous injection of IL-1,. Anti,IL-17 or control antibodies were administered during arthritis induction. Cytokine expression was evaluated by intracellular cytokine staining of synovial lymphocytes, by polymerase chain reaction analysis of RNA extracted from lymph node cells, and by enzyme-linked immunosorbent assay of cell culture supernatants. Th17 differentiation of naive CD4+ T cells was assessed in cocultures with macrophages from arthritic mice. Results Anti,IL-17 antibody administered during acute arthritis markedly reduced disease, indicating that the model is IL-17 dependent. IL-17 messenger RNA (mRNA), but not protein, was detected in draining lymph node CD4+ T cells and preceded joint inflammation. In addition, mRNA for Th17 cell,stimulatory cytokines (transforming growth factor ,, IL-6) and Th17 cell,inhibitory cytokines (interferon-,, IL-4) was detected in lymph nodes following injection of mBSA and IL-1,. Th17 cells were clearly identified in the inflamed synovium at the peak of disease. Synovial macrophages supported Th17 cell generation from naive CD4+ T cell precursors stimulated via CD3 in vitro and produced high levels of IL-6. In contrast, peritoneal macrophages failed to induce Th17 cell differentiation and produced less IL-6. Conclusion These results suggest that Th17 cell differentiation is initiated in draining lymph nodes but that IL-17,producing cells are restricted to the inflamed synovium, being generated in response to local cytokines produced by inflammatory macrophages. [source]

Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice

Manfred Kneilling
Objective Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis. Methods Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse,derived serum or control serum in wild-type Kit+/Kit+ mice, congenic mast cell,deficient KitW/KitW - v mice, or mast cell,deficient KitW/KitW - v mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated ,v,3 integrin using 18F,galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, ,3, and ,-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice. Results Comparing wild-type mice, mast cell,deficient KitW/KitW - v mice, and mast cell,reconstituted KitW/KitW - v mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and ,v,3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented ,v,3 integrin activation, angiogenesis, and joint destruction. Conclusion Mast cell engraftment fully restores susceptibility to ,v,3 integrin activation, angiogenesis, and joint destruction in GPI antibody,induced arthritis. Importantly, selective mast cell stabilization prevents ,v,3 integrin activation, angiogenesis, and joint destruction. [source]

Functional and prognostic relevance of the ,173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis

Fabrizio De Benedetti
Objective To address the functional and prognostic relevance of the ,173 single-nucleotide G-to-C polymorphism of the macrophage migration inhibitory factor (MIF) gene in patients with systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) by evaluating its association with serum and synovial fluid levels of MIF, with glucocorticoid requirement, and with the outcome of the disease. Methods A total of 136 patients with systemic-onset JIA were studied, including 98 patients from the British Paediatric Rheumatology Study Group's National Repository for JIA and 38 patients who were followed up at the IRCCS Policlinico San Matteo (Pavia, Italy) and the IRCCS G. Gaslini (Genoa, Italy). The MIF-173 polymorphism was genotyped using SnaPshot ddNTP primer extension and capillary electrophoresis. MIF levels were measured by enzyme-linked immunosorbent assay. The evaluation of the association of the MIF-173 polymorphism with outcome was performed only in Italian patients who were followed up for >5 years, by analyzing retrospectively 1) the number of joints with active arthritis and the number of joints with limited range of motion; 2) the score, at the last visit, on the Italian version of the Childhood Health Assessment Questionnaire (C-HAQ); and 3) data concerning the treatment regimens during the disease course. Results Systemic-onset JIA patients carrying a MIF-173*C allele had serum and synovial fluid levels of MIF significantly higher than those in patients with the GG genotype. The duration of glucocorticoid treatment on a daily regimen was significantly longer in patients carrying a MIF-173*C allele than in MIF-173 GG homozygous patients. Moreover, the duration of clinical response to intraarticular injection of triamcinolone hexacetonide was significantly shorter in patients carrying a MIF-173*C allele. At the last visit, the numbers of joints with active arthritis, the C-HAQ scores, and the numbers of joints with limited range of motion were significantly higher in patients carrying the MIF-173*C allele. Conclusion Our study shows the functional relevance of the MIF-173 polymorphism and suggests that the MIF-173*C allele is a predictor of poor outcome in systemic-onset JIA. [source]

Effect of oral glucosamine on cartilage and meniscus in normal and chymopapain-injected knees of young rabbits

Theodore R. Oegema Jr.
Objective To determine if oral glucosamine (GlcN) improves joint biology after acute damage by a protease. Methods The effect of 8 weeks of dietary GlcN (20 or 100 mg/kg/day) on knee joint cartilage was evaluated in 2.2-kg male NZW rabbits with and without damage introduced by intraarticular injection of chymopapain (CP). Cartilage was evaluated histologically and scored according to the Mankin scale. Analyses of total hydroxyproline and glycosaminoglycan (GAG) contents and reverse transcription,polymerase chain reaction (RT-PCR) analysis of selected genes were performed. Results After 8 weeks, there was no effect of GlcN on the GAG content of normal cartilage. Both levels of GlcN treatment significantly increased the sulfated GAG content in the cartilage of the medial femoral condyle in damaged and contralateral knees, but did not change the collagen content. In CP-injected knees, there was still some loss of surface proteoglycan (PG) that was not completely corrected by dietary GlcN. Even after 8 weeks, levels of messenger RNA (mRNA) detected by RT-PCR showed changes indicative of damage and repair, such as elevated type II collagen mRNA, and these levels were not influenced by GlcN treatment. Meniscal GAG content was increased in the contralateral knee of rabbits receiving high-dose GlcN, but was decreased in those receiving no GlcN or low-dose GlcN. Neither diet nor treatment affected the meniscal collagen content. Conclusion These results suggest that oral GlcN treatment might be useful in a situation where GlcN is limiting, such as where there is a rapid replacement of cartilage PG. [source]

Repeated intraarticular injections of triamcinolone acetonide alter cartilage matrix metabolism measured by biomarkers in synovial fluid

Christophe Céleste
Abstract Although intraarticular (IA) corticosteroids are frequently used to treat joint disease, the effects of their repeated use on articular cartilage remains controversial. The aim of our study was to determine the effects of a clinically recommended dose of IA triamcinolone acetonide (TA), on synovial fluid (SF) biomarkers of cartilage metabolism. Ten adult horses, free of osteoarthritis (OA) in their radiocarpal joints, were studied. One radiocarpal joint of each horse was randomly chosen for treatment and the contralateral anatomically paired joint acted as the control. Aseptic arthrocentesis was performed weekly on both joints for 13 weeks. The initial results from the first 3 weeks of the experimental period established baseline untreated control marker levels for each joint, each being its own control. On weeks 3, 5, and 7, a sterile suspension of 12mg of TA was injected into the treated joint and an equivalent volume of sterile saline solution (0.9%) was injected into the control joint. SF was immunoassayed for biomarkers of aggrecan turnover (CS 846 & KS), types I and II collagen cleavage (C1,2C) and type II collagen synthesis (CPII). In treated joints, there was a significant increase in CS 846, KS, C1,2C and CPII epitope concentrations following IA TA injections when compared to baseline levels. There was also a significant increase in C1,2C and CPII epitope concentrations in the contralateral control joints following IA TA injections in the treated joint. Significant differences were observed between treated and control joints for all markers except CPII. These findings indicate that TA alters articular cartilage and collagen metabolism in treated and, interestingly, also in control joints, suggesting a systemic effect of the drug. Though intuitively the observed findings would favor the hypothesis that long-term IA TA treatment changes joint metabolism and this may have detrimental effects; further studies would be necessary to confirm this. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source]

Hyaluronan suppressed nitric oxide production in the meniscus and synovium of rabbit osteoarthritis model

Kenji Takahashi
Nitric oxide (NO) plays an important role in cartilage degeneration, and NO donors induce meniscus degeneration and synovium inflammation. This study evaluated the effect of intraarticular injections of hyaluronan (HA) on NO production in meniscus and synovium using an experimental osteoarthritis (OA) model. Thirty-six New Zealand white rabbits underwent unilateral anterior cruciate ligament transection (ACLT), and were divided into three groups. Four weeks after ACLT, the HA group started to receive intraarticular HA injections once a week for 5 weeks; the vehicle group started to receive the carrier of HA; and the no injection group, no treatment. All ACLT knees were harvested at the 9th week. Meniscus and synovium sections were examined by immunohistochemistry for nitrotyrosine. The pieces of these two tissues were cultured for 24 h. Culture supernatants were analyzed for nitrite concentration. The amount of NO produced by the meniscus was much larger than that produced by the synovium. NO productions in the meniscus and synovium of the HA group were significantly lower than those of the other groups. The results suggest that the inhibition of NO production in meniscus and synovium might be a part of the mechanism of the therapeutic effect of HA on OA. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source]

Ultrastructural findings after intraarticular application of hyaluronan in a canine model of arthropathy

W. Wenz
We investigated the effect of intraarticularly applied hyaluronic acid (hyaluronan) on the cartilaginous structure of experimentally induced chondromalacia patellae in dogs. For the induction of chondromalacia, we used the Pond-Nuki technique, which involved severance and resection of the anterior cruciate ligament, as a canine model of arthropathy in 27 foxhounds (three groups of nine animals each). In a pilot study, we evaluated the effect of resection of the anterior cruciate ligament with no therapy. Patellar specimens were retrieved at 3, 6, and 12 weeks postoperatively. Subsequently, we compared a treatment group that received intraarticular injections of hyaluronan with a placebo group that received saline solution. The groups were compared at 3, 6, and 12 weeks postoperatively. Three animals from the treatment and placebo groups received five injections of hyaluronan during one of the 4-week intervals (weeks 3,6, 6,9, or 12,15). Specimens were retrieved 5 weeks after the last injection. In both groups, the uninvolved contralateral knee served as a control. The specimens were taken from the medial and lateral patellar poles. Histological analysis included light microscopy and transmission electron microscopy. The structural and ultrastructural changes were assessed qualitatively and were quantified with use of a modified Mankin score. Our results indicate that chondromalacia patellae may be induced with the Pond-Nuki technique. We found a significant reduction (p < 0.01) of cartilaginous lesions in the hyaluronan group compared with the placebo group. Our results suggest that intraarticularly applied hyaluronan is effective in delaying the degenerative process of cartilage degradation. Therefore, we conclude that the use of hyaluronan may be indicated during the early stages of chondromalacia. [source]

Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection

Gregory D. Jay
Objective To investigate whether cartilage degeneration is prevented or minimized following intraarticular injections of lubricin derived from human synoviocytes in culture, recombinant human PRG4 (rhPRG4), or human synovial fluid (SF) in a rat model of anterior cruciate ligament (ACL) injury. Methods Unilateral ACL transection (ACLT) was performed in Lewis rats (n = 45). Nine animals were left untreated. The remaining rats were given intraarticular injections (50 ,l/injection) of either phosphate buffered saline (PBS) (n = 9), human synoviocyte lubricin (200 ,g/ml; n = 9), rhPRG4 (200 ,g/ml; n = 9), or human SF lubricin (200 ,g/ml; n = 9) twice weekly beginning on day 7 after injury. Joints were harvested on day 32 after injury. Histologic analysis was performed using Safranin O,fast green staining, and articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI),modified Mankin criteria. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. A 24-hour urine collection was performed on days 17 and 29 postinjury, and urinary C-terminal telopeptide of type II collagen (CTX-II) levels were measured. Results Treatment with human synoviocyte lubricin resulted in significantly lower OARSI scores for cartilage degeneration compared with no treatment or PBS treatment (P < 0.05). Increased immunostaining for lubricin in the superficial zone chondrocytes and on the surface of cartilage was observed in lubricin-treated, but not untreated or PBS-treated, joints. On day 17, urinary CTX-II levels in human synoviocyte lubricin, and human SF lubricin,treated animals were significantly lower than those in untreated animals (P = 0.005 and P = 0.002, respectively) and in PBS-treated animals (P = 0.002 and P < 0.001, respectively). Conclusion After treatment with any of the 3 types of lubricin evaluated in this study, a reduction in cartilage damage following ACLT was evident, combined with a reduction in type II collagen degradation. Our findings indicate that intraarticular lubricin injection following an ACL injury may be beneficial in retarding the degeneration of cartilage and the development of posttraumatic OA. [source]