Infectious arthritis: clinical features, laboratory findings and treatment

An infection of native joints leads generally to suppurative arthritis, which may be of one joint (monarticular) or several joints (oligoarticular). Bacteria that produce symptoms in multiple joints during bacteraemia, such as Neisseria gonorrhoeae, may also induce inflammation in the neighbouring tendon sheaths. Viral infections frequently involve multiple joints and produce inflammation without suppuration. Chronic granulomatous monarticular arthritis may occur because of infection with either mycobacteria or fungi, which must be differentiated from other causes of chronic monarticular arthritis. A sterile arthritis may occur early in infection (as with hepatitis B), or later (as with a post-infectious arthritis). Any patient presenting with an inflamed joint should have infection as a diagnostic possibility and appropriate cultures must be performed.     

Proteoglycan-induced arthritis: immune regulation, cellular mechanisms, and genetics

Rheumatoid arthritis is probably the least understood systemic autoimmune disease, and it affects approximately 1% of the human population. Several lines of evidence indicate that the effector mechanism, which initially attacks small joints, is T-cell driven. As a result, an aggressive synovial pannus develops, which destroys articular cartilage and bone, leading to massive ankylosis and deformities of peripheral joints. The disease has a progressive character, with the involvement of more and more joints. Although the target organ is the synovial joint, there is no clear evidence that any macromolecule of cartilaginous tissues, bone, or synovium, could be a preferential autoantigen. There are numerous rodent models that simulate some or many of the clinical, immunological, or histopathological features of the disease. Recently, it has become a strong working hypothesis that MHC and non-MHC genetic components share loci that are common in various autoimmune diseases, and in corresponding animal models. The most relevant animal models of rheumatoid arthritis appear to be those induced by cartilage matrix components such as type II collagen or proteoglycan aggrecan. This review summarizes our current knowledge of cartilage proteoglycan (aggrecan)-induced arthritis in mice.     

Experimental haemarthrosis in rhesus monkeys: morphometric, biochemical and metabolic analyses

The effects of a single episode of massive haemarthrosis in rhesus monkeys were studied. Autologous whole blood was injected into a femorotibial joint of 16 anaesthetized monkeys, equally divided into four groups and killed 7 days, 2, 3 and 6 months post-injection (PI). Synovial membrane and femoral articular cartilage were analysed morphometrically and articular cartilage was further analysed biochemically and metabolically. At 7 days PI, morphometric evaluation revealed a significant increase (P less than 0.05) in synovial membrane cellularity and synovial intimal thickness of injected joints versus control joints. This change was no longer evident 2 months PI. There was also an overall (n = 16) significant increase (P less than 0.05) in femoral articular cartilage cellularity in injected joints. The average chondrocyte lacuna area of injected joints was not statistically different from the control joints. Biochemical analyses of femoral articular cartilage revealed a significant decrease in hexosamine concentration (P less than 0.05) of injected joints. There was no significant difference between the injected and control joints in hydroxyproline or total protein concentration. Metabolic analyses revealed a significant increase (P less than 0.05) in cartilage collagenous protein production by injected joints compared with control joints. There were no significant differences in cartilage or secreted total protein production between injected and control joints. There were also no significant differences in cartilage or secreted proteoglycan production between joints. Morphometric evaluation of articular tissues following massive haemarthrosis has quantified a temporary hyperplastic reaction. A significant decrease in cartilage hexosamine concentration in haemarthrotic joints suggests this is a crucial biochemical event in the pathogenesis of blood-induced cartilage destruction.     

Common principles underlying the control of rapid, single degree-of-freedom movements at different joints

Studies of rapid, single degree-of-freedom movements have shown different changes in electromyographic patterns for movement tasks that appear very similar (e.g., movements over different ranges of distance). However, it is not clear whether these differences are a result of joint-specific control schemes or whether they are instead due to the limited range of task parameters studied relative to the mechanical constraints of each joint (e.g., short compared with long movements relative to the range of motion of a particular joint). In this study, we measured and compared the kinematic trajectories and electromyograms recorded during various movement tasks at the wrist, elbow, and ankle. Subjects performed movements over a wide range of distances “as fast as possible,”“at a comfortable speed,” and against two inertial loads (at the elbow only), and they performed movements over a fixed distance at three different speeds at the wrist and ankle. For fast movements we show that, in spite of some joint-specific differences, the basic pattern of electromyographic (EMG) modulation is similar at all three joints; for example, the agonist EMG burst transitions from a fixed duration to an increasing duration with increasing movement distance at all three joints. Moreover, the distance at which this transition occurs in one joint relative to the distance at which this transition occurs in the other two joints is consistent across subjects. The transition occurs at the shortest distance at the ankle and the longest distance at the wrist. In general we suggest that the data are consistent with a single set of control rules applied at all three joints, with the biomechanical constraints at each joint accounting for the differences in the EMG and kinematic patterns observed across joints. Received: 3 September 1996 / Accepted: 10 June 1997     

Joint involvement patterns in nodal versus erosive osteoarthritis of the hands

The aim of this study was to evaluate the joint count for affected joints and involvement distribution in erosive osteoarthritis (EOA) versus nodal osteoarthritis (NOA) of the hands in patients matched for sex, age, and disease duration. After recruitment of 101 consecutive outpatients affected with EOA, 101 patients affected by NOA were selected and matched for age, sex, and disease duration. Joint count for distal interphalangeal (DIP), proximal interphalangeal (PIP), and first carpo-metacarpal (CMC-1) joints, presenting Kellgren and Lawrence grade 2-4 OA, was performed. In our study, the number of affected joints was higher in NOA, with significant differences for some articular districts, especially in PIP joints of the fourth finger, and DIP joints of the second, third and fourth fingers.     

Clinical microbiological, and histological manifestations of Streptobacillus moniliformis-induced arthritis in mice.

Intravenous inoculation of Streptobacillus moniliformis into mice resulted in an infection in which the predominant feature was progressive polyarthritis that rendered some joints immobile within 6 months. No migration of arthritis from joint to joint or remission and exacerbation were apparent. Viable organisms were apparently removed by the host from blood, liver, and spleen within 28 days post inoculation but persisted in joints for approximately 6 months in some animals. Specific antibody was detectable by complement fixation 7 days post-inoculation and persisted throughout the course of the disease. The inflammatory responses, which was initiated by the appearance of neutrophils in the joint space within 24 h of inoculation, culminated in obliteration of the joint space by fibrosis and exostosis.     

Borrelia burgdorferi migrates into joint capsules and causes an up-regulation of interleukin-8 in synovial membranes of dogs experimentally infected with ticks.

Twenty 6-week-old specific-pathogen-free beagles were infected with Borrelia burgdorferi by tick challenge, and five uninfected dogs served as controls. During the study, all dogs were monitored for infection, clinical signs, and antibody response against B. burgdorferi. During episodes of lameness or postmortem, synovial fluids from each dog were examined for volume, cell number, polymorphonuclear leukocyte (PMN) content, cell viability, and chemotactic activity. Twenty-five tissues collected postmortem from each dog were tested for interleukin-8 (IL-8) mRNA, tumor necrosis factor alpha (TNF-alpha) mRNA, presence of live spirochetes, and histopathological changes. Thirteen infected dogs (group A), which seroconverted rapidly (maximum titers within 50 to 90 days), developed acute and severe mono- or oligoarthritis almost exclusively in the limb closest to the tick bite (median incubation period, 66 days). Synovial fluids of the arthritic joints collected during episodes of lameness had significantly elevated volume, cell count, PMN proportion, cell viability, and chemotactic activity for PMNs. The remaining joints of the same animals contained synovial fluids with elevated chemotactic activity and cell viability. Twelve dogs tested positive for IL-8 mRNA in multiple tissues (synovia, pericardium, and peritoneum), and 10 dogs expressed TNF-alpha mRNA, but only in the tributary lymph nodes of the inflamed joints. Histological examinations revealed severe poly- or oligoarthritis and moderate to severe cortical hyperplasia in draining lymph nodes of the inflamed joints in all 13 dogs. Seven infected dogs with mild or no clinical signs (group B) seroconverted slowly (peak titers after 90 days), and only some joint fluids showed chemotactic activity, which on average was lower than that in inflamed and noninflamed joints from dogs in group A. Four dogs expressed IL-8 mRNA (in the synovia and pericardium), and three dogs had TNF-alpha mRNA in tributary lymph nodes. Histologically, nonsuppurative arthritis was found in multiple joints, and mild to moderate cortical hyperplasia was found in draining lymph nodes. Five uninfected dogs without lameness (group C) had normal synovial fluids and tissues. In all infected dogs, live spirochetes were demonstrated more frequently in tissues of the somatic quadrant closest to the tick bite than in tissues further from the site of infection, suggesting that dissemination of B. burgdorferi occurs more by migration than by blood-borne spread. From these studies employing a canine model of B. burgdorferi infection, we conclude that IL-8 is involved in the pathogenesis of acute Lyme arthritis.     

400例男性成人正常掌、指骨和关第的X线测量分析

作者报告了４００例正常男性成人掌、指骨长度及其比值，指间关节、掌指关节、掌腕关节间隙宽度的Ｘ线测定结果。作为成人的正常值，测定结果对某些疾病的诊断具有一定价值。     

Descriptive and functional morphology of the neck and forelimb of the striped hyena (Hyaena hyaena, L. 1758)

The musculature of the neck and the forelimb of Hyaena hyaena is described and the biomechanical implications of some morphological aspects of muscles and skeleton are discussed. The extensors of the head and neck, the protractors and retractors of the forelimb and the extensors of the shoulder, elbow and carpal joints are relatively stronger developed than those in Canidae and Felidae. Moreover these muscles have larger moments about the joints. This is considered as an adaptation to lifting and carrying large and heavy prey or carrion.     

Role of Tumor Necrosis Factor Alpha, Interleukin-1β, and Interleukin-6 in a Mouse Model of Group B Streptococcal Arthritis

Intravenous inoculation of CD1 mice with 10(7) CFU of type IV group B Streptococcus (GBS IV) results in a high incidence of diffuse septic arthritis. In this study the roles of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in articular pathology were evaluated. Cytokine levels were quantified in the serum and joints by enzyme-linked immunosorbent assay in mice injected with GBS IV and tested or not tested with pentoxifylline (PTF), a methylxanthine that affects cytokine production. PTF was administered intraperitoneally at a dose of 1 mg/mouse (50 mg/kg of body weight) 1 h after GBS infection and then at 24-h intervals for 4 days. High levels of IL-1beta and IL-6, but not TNF-alpha, were detected in the joints of mice injected with GBS IV from 5 to 15 days after infection, when articular lesions were most frequent and severe. IL-1beta and IL-6 concentrations in the joints significantly (P < 0.001) exceeded those detected in the serum, confirming a strong local production. PTF treatment resulted in a strong reduction of cytokine production and in a marked decrease in both the incidence and severity of arthritis. Inoculation of exogenous murine recombinant IL-1beta or IL-6 in mice treated with GBS IV plus PTF resulted in an incidence and severity of articular lesions similar to those obtained with inoculation of GBS IV alone. No significant effect was obtained with TNF-alpha administration. These data show a strong involvement of IL-1beta and IL-6, but not TNF-alpha, in the pathogenesis of GBS arthritis.     

腰椎椎间关节滑膜皱襞的解剖学研究及成人儿童的比较

目的：研究腰椎椎间关节滑膜皱襞的解剖学组织结构，探讨其临床价值。方法：对24具成人腰椎脊柱标本和40具儿童腰椎脊柱标本的解剖，观测腰椎间关节内滑膜皱襞的结构。结果：无论成人还是儿童，各腰椎间关节均可出现滑膜皱襞。两者比较，成人滑膜皱襞的出现率为85．9％高于儿童（35．9％），且成人以大中型滑膜皱襞为主，而儿童以小型为主。成人滑膜皱襞主要出现在外上（14．6％）、外下（16．6％）及外侧（17％），而儿童主要出现在上（20_3％）、下缘（27．1％），成人与儿童的滑膜皱襞的形态均以片状为主。结论：成人腰椎椎间关节滑膜皱襞的出现率高，以大中型滑膜皱襞为主，这很可能是腰椎椎间关节滑膜皱襞嵌顿多见于成人，而儿童少见的解剖学基础，也可能是成人较儿童腰背痛多见的原因之一。     

Anatomical variations in the tendon sheath of the first compartment

Using Hiranuma’s classification, we carefully examined anatomical variations in the first compartments of 246 human wrist joints from 124 cadavers. Morphological examinations were conducted to determine the number of accessory tendons and the existence of dissepiments for the extensor pollicis brevis (EPB) and abductor pollicis longus (APL) tendons. Anatomical variations of EPBs and APLs were grouped together by type, and appearance ratios were calculated based on Hiranuma’s classification. Of the 246 wrist joints, 156 were categorized as normal type (63.4%), 57 as complete dissepiment type (23.2%), 22 as incomplete dissepiment type (8.9%), and 11 as EPB-lacking type (4.5%). Accessory tendons were identified in both the EPB and the APL tendons of most cadavers, and the incidence of dissepiment in tendon sheaths was approximately 33%. Sixty-six of the 193 wrist joints (34.2%) showed equal numbers of right and left accessory tendons. However, the number of EPB accessory tendons was higher than in previous studies, and in all cases some kind of dissepiment was observed in the APL and EPB. The number of EPB and APL accessory tendons showed no clear differences by gender, age, or right and left specificity.     

Immobilization-Induced Cartilage Degeneration Mediated Through Expression of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor,and Chondromodulin-I

Immobilization results in thinning of the articular cartilage and cartilage degeneration, although the exact mechanisms are not clear yet. Hypoxia is thought to contribute to the degeneration of articular cartilage. We investigated the roles of hypoxia inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), and the newly cloned antiangiogenic factor, chondromodulin-I (ChM-1), in cartilage degeneration in immobilized joints. Male Wistar rats (n = 30, 12-week-old) were divided randomly into the control group (n = 10), immobilization group (n = 10), and continuous passive motion (CPM) group (n = 10). In the immobilization group, the ankle joints were fixed in full plantar flexion with plaster casts for 4 weeks. In the CPM group, the ankle casts were removed during the immobilization period and the ankle joints were subjected to CPM. Significant thinning of the articular cartilage was noted in the immobilization group but not in the control or CPM group. In the immobilized group, vascular channels were found in the area between the calcified cartilage zone and the subchondral bone. The densities of HIF-1α—and VEGF-immunostained cells were higher in the immobilized group than the other two groups. In contrast, low expression of ChM-1 was detected in the articular cartilage of the immobilized group compared with the control and CPM group. Our results showed that immobilization induces thinning of the articular cartilage and appearance of vascular channel, in areas with balanced expression of HIF-1α/VEGF and ChM-1.     

Immunoglobulin G from anti-glucose-6-phosphate isomerase antibodies positive patient with rheumatoid arthritis induces synovitis in cynomolgus monkeys

Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) solely induce arthritis in mice. High titers of anti-GPI Abs are found in some patients with rheumatoid arthritis (RA), but their pathogenic role remains elusive. The aim of this study was to evaluate the pathogenic role of anti-GPI Abs in cynomolgus monkeys. IgG fractions were separated from sera of anti-GPI Abs-positive RA patients and healthy subjects and directly injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. At day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from monkey joints. In monkey joints, IgG including anti-GPI Abs resulted in recruitment of granulocytes and mononuclear cells, strong deposition of human IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients including anti-GPI Abs may play a crucial role in the generation of synovitis in monkeys, although the pathogenesis of anti-GPI Abs in RA patients is still uncertain.     

Lyme borreliosis in the severe combined immunodeficiency (scid) mouse manifests predominantly in the joints, heart, and liver.

The authors describe the histopathologic evolution of Lyme disease in severe combined immunodeficiency (scid) and normal C.B-17 and C57BL/6 mice inoculated with Borrelia burgdorferi. Starting on day 7 after inoculation, all scid mice infected subcutaneously in the tail with a low-passage European tick isolate of B. burgdorferi had clinical evidence of arthritis characterized by reddening and swelling of tibiotarsal joints. Later on, other joints, ie, metatarsal and ulnacarpal joints were also affected. The infection of scid mice resulted in a persistent spirochetemia and the development of a multisystem disease with chronic progressive inflammation of joints, heart, and liver. Major histopathologic alterations included 1) severe joint lesions, characterized by the presence of hyperplastic inflamed synovial lining cells associated with the erosion and destruction of cartilage and/or bone; 2) pancarditis with infiltrations of mononuclear cells in the endocardium, myocardium, and pericardium; and 3) hepatitis with mononuclear cell infiltrations confined to the portal field and central vein, granulomatous reactions, and eventually the development of liver fibrosis. In addition, smaller more confined lesions were found in kidneys, lung, brain, and striated muscle. The inflammatory infiltrates in the various organs were associated mostly with Mac-1+ cells, largely monocytes and macrophages, as well as some polymorphonuclear leukocytes, but not B and T lymphocytes. Infective spirochetes could be readily isolated from blood and joints and were found at the site of inoculum and the myocardium. In contrast, subcutaneous inoculation of normal C.B-17 or C57BL/6 mice with spirochetes in general did not result in clinical signs of arthritis. Only 10% to 20% of the C57BL/6 mice, but none of the C.B-17 mice, showed clinical evidence of oligoarthritis, which appeared not before day 36 after inoculation. In general, the infection of normal mice resulted in minimal lesions in various organs, and no spirochetes could be visualized or reisolated from their tissues. The data demonstrate that Lyme borreliosis may develop in mice in the absence of detectable specific B and T cells and thus suggest an immunologic control of the disease in this species. The scid mouse model therefore can be used to define the components of the immune system responsible for the suppression and/or the progression of the disease.     

Rapid spread of mannan to the immune system,skin and joints within 6 hours after local exposure

Psoriasis (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are common diseases dependent on environmental factors that activate the immune system in unknown ways. Mannan is a group of polysaccharides common in the environment; they are potentially pathogenic, because at least some of them induce Ps-, PsA- and RA-like inflammation in mice. Here, we used positron emission tomography/computed tomography to examine in-vivo transport and spread of mannan labelled with fluorine-18 [¹⁸F]. The results showed that mannan was transported to joints (knee) and bone marrow (tibia) of mice within 6 h after intraperitoneal injection. The time it took to transport mannan, and its presence in blood, indicated cellular transport of mannan within the circulatory system. In addition, mannan was filtered mainly through the spleen and liver. [¹⁸F]fluoromannan was excreted via kidneys, small intestine and, to some extent, the mouth. In conclusion, mannan reaches joints rapidly after injection, which may explain why mannan-induced inflammatory disease is targeted to these tissues.     

Functional distinction between CXC chemokines, interleukin-8 (IL-8), and growth related oncogene (GRO)alpha in neutrophil infiltration.

Interleukin-8 (IL-8: CXCL8) and growth related oncogene alpha (GROalpha: CXCL1) are members of the CXC chemokines. In the present study, we explored the functional distinction between these CXC chemokines in the regulation of neutrophil infiltration. Injection of either rabbit IL-8 or GROalpha (10 microg each) into rabbit knee joints resulted in a massive neutrophil infiltration in the joints. At their peak time point (6 hours), the number of neutrophils induced by IL-8 was more than that induced by GROalpha. Each chemokine induced the other chemokine in the joints. TNFalpha activity was induced in the joints after administration of GROalpha, but not IL-8. Treatment with anti-GROalpha mAb and/or anti-TNFalpha mAb failed to inhibit IL-8-induced neutrophil infiltration. In contrast, either anti-IL-8 IgG or anti-TNFalpha mAb decreased GROalpha-induced response, and the inhibition was further enhanced by coadministration of these antibodies. Thus, it appears that IL-8 acts directly, whereas GROalpha acts indirectly, in part, on neutrophil infiltration. The distinct difference in TNFalpha production between IL-8 and GROalpha was further investigated. In vitro, GROalpha induced TNFalpha activity in cultured synovial cells, the cells producing TNFalpha in the joints after GROalpha-injection. However, IL-8 failed to produce TNFalpha activity from the cells, although equivalent levels of the mRNA expression were induced by IL-8 as compared with GROalpha. When recombinant rabbit TNFalpha was incubated with synovial fluids obtained at 2 hours after IL-8 injection, the resultant TNFalpha activity was significantly decreased, an event that was completely restored by a serine protease inhibitor, phenylmethylsulphonyl fluoride (PMSF). Furthermore, TNFalpha activity was unveiled in the joints when IL-8 was intra-articularly injected with PMSF. These data suggest that TNFalpha is degraded by serine protease(s) in the case of IL-8. Taken together, the data clearly demonstrate the functional distinction between IL-8 and GROalpha, which may influence the inflammatory responses.     

Prevalence of sesamoid bones in the interphalangeal joint of the thumb and fingers: A Radiographic Study

The prevalence of sesamoid bones in the hands has been reported in some previous articles. Most of them, however, have reported sesamoid bones of the metacarpophalangeal joint of the hand and of the interphalangeal (IP) joint of the thumb. The present study investigates the prevalence of sesamoid bones of the IP joint of the thumb and fingers. A retrospective review of radiologic views of the IP joints in the thumb or fingers was performed, including a total of 650 patients (1,096 thumbs or fingers). Sesamoid bones were found in the IP joint of the thumb at 67% (212 of 318), while the index, middle, ring, little fingers had sesamoid bones in the proximal interphlangeal (PIP) joint at 0% (0 of 172), 0.4% (1 of 244), 0.5% (1 of 183), and 1% (2 of 179), respectively. None of the four fingers had sesamoid bones in the distal IP joint. Previous articles have described the similar prevalence to the present study, of sesamoid bones of the IP joint of the thumb, while some others reported the different prevalence. About the PIP joint, no previous articles have found a sesamoid bone. Because the lateral X‐ray view is more accurate and suitable to evaluate sesamoid bones, we used the lateral one for the present study. The knowledge that sesamoid bones occurs at these rates in the thumb IP joint and finger PIP joints is helpful to differentiate chip fractures from sesamoid bones near the IP joint, including the PIP joint. Clin. Anat. 2013. © 2012 Wiley Periodicals, Inc.     

寰枕、寰枢关节滑膜皱襞解剖观测及临床意义

目的：观察寰枕、寰枢关节中各关节有无滑膜皱襞存在，皱襞的形态、位置和组织学，探讨其临床意义。方法：对16例12岁以下小儿和8例成人防腐尸体的寰枕、寰枢关节中的各关节进行解剖观测。结果：无论成人或小儿，除了寰枢后正中关节外，其它关节均有滑膜皱襞存在，滑膜皱襞总出现率66．7％。寰枢前正中关节中皱襞位于上关节间隙，寰枕关节、寰枢外侧关节的皱襞主要分布于前外侧，多数皱襞呈月牙形。与成人相比，小儿组皱襞数量多，总出现率达72．34％(成人组仅58．3％)，小儿以大中型皱襞为主(58．35％)，成人以小型皱襞为主(62．5％)且无大皱襞。镜下观察儿童有三种不同的组织学类型，其中以脂肪型和纤维脂肪型为主(88．9％)。结论：推测在儿童寰枕、寰枢关节中有更多更大的滑膜皱襞，在受到外伤或炎症作用下，皱襞肿胀变大，位置改变，发生嵌顿，这很可能是小儿好发某些上颈椎疾病，如寰枢椎旋转畸形的解剖学基础。     

ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs

OBJECTIVE AND DESIGN: To evaluate the effect of a newly developed inhibitor of matrix metalloproteinases (MMPs), ONO-4817, on the degradation of cartilage in the guinea pig arthritis model. MATERIALS: 42 guinea pigs were used in the arthritis model. TREATMENT: Lipopolysaccharide (LPS) was injected into guinea pig knee joints. The content of proteoglycan released in synovial cavity was measured as a marker of cartilage degradation. ONO-4817, dexamethasone or indomethacin were administered orally to the animals. RESULTS: ONO-4817 showed a broad inhibitory activity against MMPs except MMP-1 and MMP-7. The oral administration of ONO-4817 dose-dependently suppressed the release of proteoglycan from the cartilage of the knee joints. CONCLUSION: This study suggests the possibility that a novel MMP inhibitor, ONO-4817 may have a therapeutic utility for MMP-related diseases.