Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease.

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast-myofibroblast transition, epithelial-mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.

Understanding Viral Infection Mechanisms and Patient Symptoms for the Development of COVID-19 Therapeutics.

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become a worldwide pandemic. Symptoms range from mild fever to cough, fatigue, severe pneumonia, acute respiratory distress syndrome (ARDS), and organ failure, with a mortality rate of 2.2%. However, there are no licensed drugs or definitive treatment strategies for patients with severe COVID-19. Only antiviral or anti-inflammatory drugs are used as symptomatic treatments based on clinician experience. Basic medical researchers are also trying to develop COVID-19 therapeutics. However, there is limited systematic information about the pathogenesis of COVID-19 symptoms that cause tissue damage or death and the mechanisms by which the virus infects and replicates in cells. Here, we introduce recent knowledge of time course changes in viral titers, delayed virus clearance, and persistent systemic inflammation in patients with severe COVID-19. Based on the concept of drug reposition, we review which antiviral or anti-inflammatory drugs can effectively treat COVID-19 patients based on progressive symptoms and the mechanisms inhibiting virus infection and replication.

Predicting Imaging Remission in Rheumatoid Arthritis: a Case-control Ultrasound Study.

BACKGROUND: To elucidate the achievement rates of imaging remission and to examine the characteristics associated with imaging remission status among patients with rheumatoid arthritis (RA) who have attained clinical remission. METHODS: Ninety-seven patients with RA patients who had attained clinical remission, defined by DAS28-ESR < 2.6 were enrolled. Power Doppler ultrasonography (PDUS) was performed on 16 joints and 2 tendons, including the first to third metacarpophalangeal, second and third proximal interphalangeal, radiocarpal (RC), second and third metatarsophalangeal joints, and extensor carpi ulnaris tendons. They were graded based on a dichotomous assessment. The clinical and laboratory data of patients who had attained imaging remission were compared to those of patients who had attained only clinical remission. RESULTS: The imaging remission rate was 51.5% in patients who had attained clinical remission. Forty-seven patients (48.5%) were PDUS positive. Power Doppler was detected most frequently in the right RC joint (n = 40). PDUS positive patients had higher evaluator global assessment (EGA) scores (P < 0.001) than PDUS negative patients. PDUS positive patients also had higher clinical disease activity index and simplified clinical disease activity index scores than PDUS negative patients. Patients who had attained imaging remission had lower pain scores and used nonsteroidal anti-inflammatory drugs less frequently. Patients who had attained imaging remission had higher rheumatoid factor (RF) and anti-cyclic citrullinated peptide levels. A low EGA score was found to be a predictor of imaging remission achievement among patients who had attained clinical remission. CONCLUSION: Only 51.5% of the patients with RA who had attained clinical remission were also in imaging remission. Patients who had attained imaging remission had lower EGA scores and higher RF levels than patients who had attained only clinical remission.

Dysregulated Autophagy Mediates Sarcopenic Obesity and Its Complications via AMPK and PGC1α Signaling Pathways: Potential Involvement of Gut Dysbiosis as a Pathological Link.

Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and PGC-1α signaling pathways are implicated in the gut microbiome-muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or PGC-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.

Anti-obesity effect of taurine through inhibition of adipogenesis in white fat tissue but not in brown fat tissue in a high-fat diet-induced obese mouse model.

This study was conducted to evaluate the anti-obesity effects of long-term taurine supplementation in a mild obese ICR mouse model and to study the mechanism by which taurine induces weight loss. Three groups of male ICR mice were fed a normal chow diet, a high-fat diet (HFD), or an HFD supplemented with 2% taurine in drinking water for 28 weeks. Body weight was measured every week. Metabolic, behavioral, and physiological monitoring were carried out using PhenoMaster at 28 weeks. Interscapular brown fat (BAT), inguinal white fat tissue (WAT), and quadriceps muscle were analyzed and compared to assess the change of gene expression related to adipogenesis. Taurine supplementation showed the trend of anti-obesity effect in ICR mice fed an HFD for 28 weeks. HFD-fed mice did not show significant difference of oxygen consumption (VO2), energy expenditure (EE), respiratory exchange rate (RER), and locomotive activity compared with those of normal chow diet fed mice. The expression of adipogenesis-related genes such as PPAR-α, PPAR-γ, C/EBP-α, C/EBP-ß, and AP2 increased in BAT and WAT, but not in muscle tissue. Taurine supplementation showed the downregulation of these genes in WAT but not in BAT or muscle. Consistently, the expression of taurine transporter (TauT) and adipocyte-specific genes such as adiponectin, leptin, and IL-6 was regulated in a similar pattern by taurine supplementation. Long-term taurine supplementation causes weight loss, most likely by inhibiting adipogenesis in WAT. TauT expression may be involved in the expression of various genes regulated by taurine supplementation.

Effects of Chronic Intake of a Low Concentration of Taurine on Physical Strength and Body Composition in Mice.

Most studies of taurine on athletic performance have been conducted at acute and high doses in rodents. These doses and duration of administration are not reasonable for normal human life. Thus, it is not valid to extrapolate these animal results to people. Dose and duration that mimic human use of taurine in normal life can help to clarify the taurine effect in humans. This study investigated whether long-term, low-dose taurine (2% taurine drinking water for 25 weeks), similar to normal taurine intake in humans, can affect endurance exercise and body composition. Twenty ICR mice were divided into two groups. The control group received normal drinking water, and the taurine treated group received 2% taurine drinking water for 25 weeks. The mice were evaluated for body composition by mass and for physical strength by treadmill exhaustion and suspension tests. The supply of chronic 2% taurine drinking water has a slight effect on weight gain. In body composition analysis, a slight increase in body weight was due to an increase in muscle mass, not an increase in body fat. However, taurine ingestion did not increase endurance exercise. In conclusion, these results indirectly suggest that acute, high-dose taurine treatment is better than long-term, low-dose treatment to increase athletic performance.

Hypocomplementemic Urticarial Vasculitis Syndrome with Membranous Nephropathy: Case Report.

Urticarial vasculitis is a rare disorder that principally manifests with recurrent urticarial, sometimes hemorrhagic, skin lesions and/or angioedema. Its clinical presentation is not always limited to cutaneous lesions and it can potentially affect other organs, such as the joints, lungs, kidneys, and eyes. Systemic involvement can either be present at the onset of disease or develop over time. In cases with systemic manifestations, urticarial vasculitis is more likely to be associated with a low complement level. We present the case of a teenage boy with hypocomplementemic urticarial vasculitis syndrome (HUVS) that occurred shortly following swine-origin influenza A virus infection in 2009. Afterwards, HUVS was systemically complicated with myositis and membranous nephropathy that developed several months and about 2 years after its onset, respectively. A combination of glucocorticoid and immunosuppressive agents has been used to effectively control disease activity.

Complete Remission of Nephrotic Syndrome Without Resolution of Amyloid Deposit After Anti-Tumor Necrosis Factor α Therapy in a Patient With Ankylosing Spondylitis.

In secondary amyloid A amyloidosis resulting from rheumatologic diseases, tumor necrosis factor α blockers have been reported to be effective in the treatment of both arthritis and amyloidosis. However, there have been few reports concerning the alterations of renal tissue histology before and after long-term tumor necrosis factor α blockers therapy in secondary renal amyloidosis. We report the histological change after tumor necrosis factor α blocker therapy in patient with amyloid A amyloidosis and nephrotic syndrome secondary to underlying ankylosing spondylitis. The patient achieved complete remission of nephrotic syndrome after 17 months of etanercept treatment. We performed the second kidney biopsy after 40 months, and there was little change in the degree of amyloid deposition in the mesangial area and capillary loops compared with the first biopsy. The interstitial inflammation and foot process effacement, however, were fully recovered.

Taurine chloramine modulates the expression of adipokines through inhibition of the STAT-3 signaling pathway in differentiated human adipocytes.

To examine the possible role of taurine chloramine (TauCl) in modulating the expression of adipokines in adipose tissue associated with obesity, we evaluated the effect of TauCl in human differentiated adipocytes in response to IL-1ß. To study the physiological effects of TauCl on adipokine expression, differentiated adipocytes were treated with IL-1ß in the presence or absence of TauCl at concentrations ranging from 200 to 600 µM for 7 days. Cell culture supernatants and total RNA were analyzed by ELISA and real-time PCR, respectively, to determine protein and mRNA levels of adipokines, including adiponectin, leptin, IL-6, and IL-8. Levels of proteins involved in relevant signaling pathways were investigated by western blotting. Stimulation with IL-1ß significantly decreased levels of adiponectin and leptin in adipocytes, but increased levels of IL-6 and IL-8 in a dose-dependent manner. Treatment with TauCl significantly reversed the modulation of adipokine expression by inhibiting STAT-3 signaling in IL-1ß-stimulated adipocytes, independent of MAPK signaling. TauCl treatment more significantly modulated the expression of adipokines in adipocytes stimulated with IL-1ß than that of non-stimulated adipocytes, suggesting that TauCl plays a significant role in modulating the expression of adipokines under inflammatory conditions. In conclusion, TauCl and other taurine derivatives that inhibit the STAT-3 signaling pathway can modulate expression of adipokines and thus may be useful as therapeutic agents for obesity-related diseases.

Renal involvement in ankylosing spondylitis: prevalence, pathology, response to TNF-a blocker.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily involving the spine and sacroiliac joint and rarely the kidneys. This study aimed to define the clinical and histological features and biology of renal disease in AS. We reviewed the medical records of 681 patients diagnosed with AS from November 2008 to November 2009. Baseline characteristics and laboratory and urinalysis results were reviewed. We identified patients with proteinuria or hematuria and analyzed their risk factors. After providing informed consent, 6 patients underwent a renal biopsy to determine the cause of proteinuria or hematuria. Of the 681 enrolled patients, 547 were men and 134 were women; 81 % were HLA B27 positive, and 8 % had abnormal urinalysis findings (proteinuria, 5.9 %; hematuria, 2.8 %; both, 0.7 %). Incidences of peripheral arthritis and uveitis were 29 % and 18.6 %, respectively. Immunoglobulin (Ig)A and uric acid levels were significantly different between patients with and without proteinuria. Erythrocyte sedimentation rate (ESR), total cholesterol, creatinine, and C-reactive protein (CRP) levels were not statistically significantly different between the 2 groups nor were there any significant differences in IgA, uric acid, ESR, total cholesterol, creatinine, and CRP levels between patients with and without hematuria. Six patients who had >1 g/day proteinuria underwent a renal biopsy; 2 were diagnosed with IgA nephropathy, 1 with amyloidosis, and 3 with non-specific glomerulonephropathy. In the amyloidosis patient, severe proteinuria was the dominant feature. For patients with renal amyloidosis and other forms of glomerulonephritis who initially had normal creatinine levels, tumor necrosis factor (TNF)-alpha blocker therapy resolved proteinuria, but this was not the case for patients with initial renal insufficiency. Renal involvement is not a rare complication of AS, and prognoses differ depending on kidney pathology. Serum levels of uric acid and IgA may predict renal involvement in AS. In cases where abnormal urine sediment is identified, renal biopsy is required to determine prognosis and decide the treatment protocol. Baseline serum creatinine level is important for predicting treatment response.

Taurine may not alleviate hyperglycemia-mediated endoplasmic reticulum stress in human adipocytes.

In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress. Hyperglycemia-induced ER stress has not been studied in adipocyte differentiation and adipokine expression. Taurine has been known to protect the cells against ER stress. This study examined the effect of taurine on ER stress-induced adipocyte differentiation and adipokine expression to explain the therapeutic effect of taurine on diabetes and obesity. To do this, human preadipocytes were differentiated into adipocytes, in the presence or absence of taurine, under ER stress conditions. Changes in adipokine expression in adipocytes stimulated with IL-1ß were investigated in the presence or absence of taurine. Human preadipocytes were treated with thapsigargin (10 nM) or high glucose concentrations (100 mM) as ER stress inducers during differentiation into adipocytes. Thapsigargin inhibited the differentiation of adipocytes in a dose-dependent manner, but the high glucose concentration treatment did not. Taurine 100 mM treatment did not block the inhibition of differentiation of preadipcytes into adipocytes. Furthermore, the high glucose concentration treatment inhibited the expression of adiponectin and increased the expression of leptin in human adipocytes. However, taurine treatment did not affect the expression of two adipokines. In conclusion, the therapeutic mechanism of taurine in diabetes and obesity does not appear to occur by alleviating hyperglycemia-mediated ER stress. To clarify the molecular mechanism by which taurine improves diabetic symptoms and obesity in animal models, the protective effect of taurine against hyperglycemia- or overnutrition-mediated ER stress should be further evaluated under various conditions or types of ER stress.

Effect of taurine chloramine on differentiation of human preadipocytes into adipocytes.

We investigated whether taurine chloramine (TauCl), which is -endogenously produced by immune cells such as macrophages that infiltrate adipose tissue, affects the differentiation of preadipocytes into adipocytes or modulates the expression of adipokines in adipocytes. To study the physiological effects of TauCl on human adipocyte differentiation and adipokine expression, preadipocytes were cultured under differentiation conditions for 14 days in the presence or the absence of TauCl. Differentiated adipocytes were also treated with TauCl in the presence or the absence of IL-1ß (1 ng/ml) for 7 days. The culture supernatants were analyzed for adipokines such as adiponectin, leptin, IL-6, and IL-8. At concentrations of 400-600 µM, TauCl significantly inhibited the differentiation of human preadipocytes into adipocytes in a dose-dependent manner. It did not induce the dedifferentiation of adipocytes or inhibit fat accumulation in adipocytes. Expression of major transcription factors of adipogenesis and adipocyte marker genes was decreased after treatment with TauCl, in agreement with its inhibition of -differentiation. These results suggest that TauCl may inhibit the differentiation of -preadipocytes into adipocytes. Thus, TauCl or more stable derivatives of TauCl could potentially be a safe drug therapy for obesity-related diseases.

A case of myotonic dystrophy with electrolyte imbalance.

Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.

Effects of aging-induced obesity on the transcriptional expression of adipogenesis and thermogenic activity in the gonadal white adipose, brown adipose, and skeletal muscle tissues.

PURPOSE: Aging is closely associated with chronic metabolic diseases, such as obesity, which lead to increased adiposity, skeletal muscle wasting, and imbalanced cellular energy metabolism. However, transcriptional profiles representing energy imbalances in aging-induced obesity are not fully understood. Thus, this study aimed to investigate the candidate genes predominantly regulated in aging-related obesity in spontaneously aged mice. METHODS: Male C57BL/6J mice were divided into three age groups according to age: 2- (young), 12- (middle-aged), and 24- (old) months. Body weight and body composition parameters were measured in all mice. Gonadal white adipose tissue (gWAT), brown adipose tissue (BAT), and skeletal muscle (SM) were dissected and weighed. The target tissues were assessed using biochemical and histological assays. RESULTS: Aging-induced obesity increased adipose mass and decreased SM weight through processes of adipocyte hypertrophy; however, recruitment of modulating adipogenesis-inducing transcription factors did not occur. Among adipokines, leptin level was greatly increased in the gWAT during aging. Interestingly, the ß2-adrenergic receptor had a higher affinity than the ß3-adrenergic receptor in aging-induced obesity. For the thermogenic regulation through ß-adrenergic receptors (ß-ARs), a declined uncoupling protein-1 (UCP-1) in the BAT was relevant to aging-induced obesity. CONCLUSION: Aging-induced obesity increases leptin levels in adipocytes and decreases UCP-1 in BAT through ß-ARs, according to transcriptional gene profiling. WAT browning increases energy expenditure due to exercise training adaptations. Further research is needed to discover more effective methods, such as exercise, against aging-induced obesity.

Hypoxia differentially affects IL-1ß-stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1α-dependent manner.

OBJECTIVES: To further understand the expression regulation of MMP-1 and MMP-13 under physiological and pathological conditions, we investigated the combined effects of hypoxia and pro-inflammatory stimuli on the expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. METHODS: Synovial fibroblasts were cultured under either hypoxic or normoxic conditions in the presence of IL-1ß stimulation. The culture supernatant was analysed for secreted levels of VEGF, MMP-1 and MMP-13. Their gene expression was quantified with real-time and semi-quantitative PCR. Another group of cells was transfected with small-interfering RNA (siRNA) specific for hypoxia-inducible factor-1 α (HIF-1α). The protein levels of HIF-1α were detected by western blot analysis. RESULTS: In response to 10 ng/ml of IL-1ß under normoxia, the levels of MMP-1 and MMP-13 increased compared with the levels observed under hypoxia. IL-1ß stimulation under hypoxia induced a 2-fold increase in the level of MMP-1 and a 2-fold decrease in the level of MMP-13 compared with cells cultured under normoxia. A similar pattern of differential expression for MMP-1 and MMP-13 was observed with 1 and 5 ng/ml IL-1ß, but not at 0.1 ng/ml. The differential expression of MMPs under the combined effect of IL-1ß and hypoxia was significantly attenuated by silencing HIF-1α with siRNA. CONCLUSIONS: Hypoxia in arthritic joints may differentially affect the IL-1ß-stimulated expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. This effect is dependent on HIF-1α expression. This hypoxia-mediated differential effect should be taken into consideration when testing the efficiency of therapies that target HIF-1α.

Implication of MMP-9 and urokinase plasminogen activator (uPA) in the activation of pro-matrix metalloproteinase (MMP)-13.

We examined whether the expression and activation of pro-matrix metalloproteinase (MMP)-1 varies from that of pro-MMP-13 in the joint fluid of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. To do this, joint fluid was collected from 34 RA and 34 OA patients. The collagenase (pro-MMP-1 and MMP-13, total MMP-1, and MMP-13), gelatinase (total MMP-2 and MMP-9), stromelysin (total MMP-3), matrilysin (total MMP-7), uPA, and tissue inhibitor of MMP (TIMP) levels were measured by ELISA. The level of total MMP-1 in RA joint fluids was similar to that of the OA joint fluid. In contrast, the level of total MMP-13 in the RA group was significantly higher than that of the OA group. Among various MMPs (MMP-2, MMP-3, MMP-7, and MMP-9), only MMP-9 was strongly associated with total MMP-13 in both RA and OA. The level of uPA was also strongly associated with MMP-13 in RA but not OA, while the level of TIMP-1 and TIMP-2 was not significantly different between RA and OA. In conclusion, MMP-9 and uPA might be involved in the activation of pro-MMP-13 through unknown mechanisms in arthritic diseases.

Increased expression of IL-1 receptors in response to IL-1ß may produce more IL-6, IL-8, VEGF, and PGE2 in senescent synovial cells induced in vitro than in presenescent cells.

Primary synovial cells with high passage number demonstrate increased production of proinflammatory mediators in response to inflammatory stimuli compared with cells with low passage number. This study used synovial cells to learn how different numbers of serial subculture passages affect the production of proinflammatory mediators in response to interleukin (IL)-1ß. Synovial cells were serially subcultured in flasks until passage 7. During cell passage, synovial cells were treated with IL-1ß for 24 h. Levels of proinflammatory mediators were analyzed by ELISA, real-time PCR, and Western blot. Synovial cells at passage 7 had elongated morphology and higher activity of ß-galactosidase, a marker of senescence, than those at passage 3. Production of IL-6, IL-8, vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE(2)) in response to IL-1ß was significantly increased in cells at passage 7 compared with passage 3. To evaluate the mechanism of this different response, IL-1 receptor expression was studied in cells stimulated with IL-1ß. Compared with cells at passage 3, cells at passage 7 had stronger expression of IL-1 receptors 1 and 2, as well as significantly increased expression of both receptors, in response to IL-1ß. This finding suggests that differential production in response to inflammatory stimuli associated with cell passages should be considered when in vitro experiments are used to evaluate the production levels of proinflammatory mediators.

Arthritic disease is more severe in older rats in a kaolin/carrageenan-induced arthritis model.

This study examined in an arthritis animal model whether elderly onset rheumatoid arthritis (EORA) is a more severe disease than younger onset rheumatoid arthritis. Arthritis was induced by injecting 5% kaolin/carrageenan into the left tibiotarsal ankles of 18-month-old and 4-week-old rats. Various parameters were measured to evaluate the arthritic progression of kaolin/carrageenan-induced arthritis in the rats. Immunohistochemical staining of arthritic joints was performed to determine the degree of inflammation in old and young rats. Measurements of ankle volume and thickness, arthritic index, number of squeaks, and the paw pressure test showed the 18-month-old rats had more severe disease than the young rats in a kaolin/carrageenan-induced arthritis model. The degree of inflammation and MMP-1 expression of arthritic joints in old rats was significantly higher than that of young rats based on histological evaluation with hematoxylin and eosin (H&E) staining and immunochemistry. More severe disease symptoms were found in old rats with EORA, but the molecular mechanisms still remain to be elucidated. Understanding the molecular mechanisms will be helpful to develop clinical protocols to efficiently treat patients with EORA, which is difficult to control with current protocols.

Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis.

This study was performed to provide evidence, albeit indirectly, as to which matrix metalloproteinases (MMPs), among the gelatinases MMP-2 and MMP-9 and the collagenases MMP-1 and MMP-13, play a more proactive role in the angiogenic process in arthritic joint. Joint fluid was collected from 33 patients with rhuematoid arthritis (RA) and osteoarthritis (OA), and protein (MMPs and vascular endothelial growth factor (VEGF)) levels were measured by ELISA, and the association of MMPs with VEGF was evaluated in joint fluid of patients with RA or OA. The levels of collagenases (total MMP-1 and total MMP-13) and gelatinases (total MMP-2 and total MMP-9) in RA joint fluid were significantly higher than those in OA fluid. Total MMP-9 levels were significantly associated with VEGF levels in RA fluids, but not in OA fluid, while total MMP-13 levels were strongly associated with VEGF levels in both RA and OA fluid. However, total MMP-2 and total MMP-1 levels were not associated with VEGF levels in either RA or OA joint fluid. Our results indirectly suggest that in RA and OA, MMP-9 and MMP-13 may play a more important role in angiogenesis than MMP-2 and MMP-1.