Progressive Joint Disease Research Articles

Response of osteoarthritis biomarkers after a rehabilitation program: study protocol

<p class="abstract"><strong>Background:</strong> Knee osteoarthritis is a progressive degenerative joint disease and remains a leading cause of pain, physical impairment and decline in health-related quality of life in adults. Despite its incidence being amongst the highest in chronic diseases, effective biomarkers are not available to assist in its management. The main goal of this study is to identify mediators that serve as biomarkers and investigate if the levels of these biomarkers will be correlated to the efficacy of a rehabilitation program.</p><p class="abstract"><strong>Methods:</strong> This is a prospective cohort study with 65 participants. Patients with mild-to-moderate symptomatic knee osteoarthritis will be recruited. The Rehabilitation Program will consist of three session/week during eight weeks. Assessment about functional evaluation will be performed before and after treatment, using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQOL-5D (Euro quality of life - five dimension) scales, Visual Analog Scale (VAS), and physical function tests (time up and go, isometric strength testing and kinematic gait analysis). Serum levels of classical pro-inflammatory cytokines, hyaluronan and high mobility group box 1 protein (HMGB-1) will be evaluated. The primary outcome is the change in WOMAC scale from baseline to end. Statistical analyses will be used to determine correlation of physical improvement and serum biomarkers. Adverse events will be monitored throughout the study.</p><p class="abstract"><strong>Conclusions: </strong>This trial expect to study the correlation between the anti-inflammatory effects of rehabilitation program derived factors that may be involved in suppressing cytokine induction via suppressing HMGB-1.</p><p class="abstract"><strong>Trial registration:</strong> Clinicaltrials.gov - NCT02964624.</p>

Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis.

Osteoarthritis (OA) is a progressive joint disease that causes significant disability and pain and for which there are limited treatment options. We posit that delivery of anabolic factors that protect and maintain cartilage homeostasis will halt or retard OA progression. We employ a peptide-based nanoplatform to deliver Wingless and the name Int-1 (WNT) 16 messenger RNA (mRNA) to human cartilage explants. The peptide forms a self-assembled nanocomplex of approximately 65 nm in size when incubated with WNT16 mRNA. The complex is further stabilized with hyaluronic acid (HA) for enhanced cellular uptake. Delivery of peptide-WNT16 mRNA nanocomplex to human cartilage explants antagonizes canonical β-catenin/WNT3a signaling, leading to increased lubricin production and decreased chondrocyte apoptosis. This is a proof-of-concept study showing that mRNA can be efficiently delivered to articular cartilage, an avascular tissue that is poorly accessible even when drugs are intra-articularly (IA) administered. The ability to accommodate a wide range of oligonucleotides suggests that this platform may find use in a broad range of clinical applications.

Effectiveness and tolerability of tramadol versus diclofenac in treatment of knee osteoarthritis: A comparative clinical study

Background: Osteoarthritis (OA) is a progressive joint disease. It causes wear and tear of the articular cartilage of the joint. It is painful and symptoms include joint pain, stiffness, and tenderness. Performing daily life activities gets affected over time. Aim and Objectives: The aim of the present study was to compare the effectiveness and tolerability of tramadol versus diclofenac in treating chronic pain due to knee OA and to determine Adverse drug reactions (ADRs) with the use of the drugs. Materials and Methods: Consecutive patients of OA reporting to our hospital with chronic knee pain aged 45–65 years were divided into two treatment groups, tramadol and diclofenac groups, and received the tramadol drug and diclofenac drug orally with doses of 50 mg and 75 mg 2 times a day, respectively, for 8 weeks. Overall improvement was evaluated through various parameters. Results: There was a 16.73% decrease in time taken to walk 100 feet in the diclofenac group and an 18.30% decrease in the tramadol group. There was a 42.85% decrease in pain score at rest in diclofenac and a 50.72% decrease in the tramadol group. A decrease in pain score during active movement was 32.4% in diclofenac and 44.8% decrease in the tramadol group. The overall incidence of ADRs reported in the study was n = 8 (16%) in the tramadol group and n = 13 (26%) in the diclofenac group. Conclusions: Tramadol was superior to diclofenac for reducing knee joint pain, stiffness, tenderness, and difficulty in daily performing tasks. There was a significant improvement in the standard of life in patients suffering from knee OA when treated with tramadol.

Study to Assess the Prescription Pattern and Quality of Life in Osteoarthritis Patients at a Tertiary Care Hospital

Introduction: Osteoarthritis (OA) often called wear and tear arthritis is a chronic progressive musculoskeletal joint disease with multifactorial aetiology, affecting millions of people around the world. It is one of the leading causes of morbidity, having major impact on Quality of Life (QoL) of the patient with substantial economic and social burden. OA can have a negative impact on health related QoL and psychological well-being of the individual. Aim: To evaluate the prescribing trends of drugs in the management of OA in a tertiary care teaching hospital and to assess the effect of pharmacotherapy on QoL of OA patients in terms of subjective and functional status using Western Ontario and McMaster Universities Arthritis index scale (WOMAC)-modified Centre for Rheumatic Disease (CRD) Pune version OA patients. Materials and Methods: Prospective observational study conducted among the OA patients in Orthopaedic Department over the period of one year between November 2014-December 2015. Adult patients of either gender diagnosed with OA for minimum period of three months were enrolled for the study. Out of 285 eligible patients, drug therapy of 256 patients’ data were analysed and they were given treatment by the treating orthopaedician. All the patients were asked to personally complete the WOMAC index scale during their first visit. They were followed-up for one month of pharmacotherapy in order to assess change in the WOMAC index scale. Data were analysed using Statistical Package for the Social Sciences (SPSS) software 16.0 version. The p-value <0.05 was considered statistically significant. Results: Among 256 patients who completed the study, the most frequently prescribed drug class was NSAIDs (82.1%). Acelofenac with Paracetamol combination (117) and Diclofenac monotherapy (44) were most commonly prescribed. Statistically significant reduction in the WOMAC (pain, stiffness and physical function) score was observed in the follow-up visit when compared to first visit (p<0.0001) after one month of pharmacotherapy in patients taking Diclofenac and Aceclofenac with Paracetamol combination. Conclusion: This study highlighted the significant improvement in QoL and significant reduction in WOMAC scores with Aceclofenac-Paracetamol combination and Diclofenac monotherapy in OA patients.

Effect of Lavender Oil Massage on Pain among Patients with Knee Osteoarthritis

Osteoarthritis (OA) is a progressive chronic joint disease with global relevance with up to 250 million people being affected from knee OA worldwide. The aim of this study was to evaluate the effect of Lavender oil massage on pain among patients with knee osteoarthritis. A convenient sample of 60 adult male and female patients who admitted to Rheumatology and Rehabilitation unit affiliated to Cairo University hospital in Egypt with confirmed diagnosis of knee OA divided into experimental (study) and control group. A quasi-experimental Time Series pre-post test non equivilant interrupted control design was utilized in the current study. Data was collected using Personal and Medical Background Information Form, Pain Numerical Rating Scaleand Lequesne Algo Functional Index of Severity. The study findings revealed that there were significant statistical differences of pain intensity score and OA severity between study and control group after application of lavender oil massage. Conclusion: Lavender oil massage was proved in this study to be effective on pain and OA severity among patients with knee osteoarthritis.

Симптоматические препараты замедленного действия (SYSADOA) – новая реальность в лечении остеоартрита

Osteoarthritis (OA) is the most common chronic progressive joint disease. Over the last years, it has been evidenced that OA is associated with an increased risk of death, which may be explained by low-intensity chronic inflammation underlying its pathogenesis, long-term pain syndrome, and high comorbidity. Considering the above, the FDA classified OA as a serious disease that requires more careful monitoring of patients and the earliest possible prescription of effective therapy in August 2018 [1].

Thumb Metacarpophalangeal Joint Arthritis.

Arthritis of the thumb metacarpophalangeal joint can be debilitating whether in isolation or in conjunction with degenerative disease at the adjacent joints. Despite its crucial role in fluid and dexterous motion of the thumb axis, little is known about the isolated incidence of pathology at this joint. Etiologies include primary, posttraumatic, and inflammatory arthritis. For early, isolated degenerative disease, arthroscopic synovectomy has been shown to yield satisfactory results. For more advanced disease, fusion is the benchmark. The literature suggests that increased flexion angles may mitigate development of trapeziometacarpal arthritis. In case of advanced arthropathy of the entire thumb axis, arthroplasty is a viable option to reduce pain, preserve motion, and thus limit progression of adjacent joint disease. Special considerations should be given to the rheumatoid thumb because a select combination of treatments for each deformity is thought to best address the unique pathomechanics.

Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

Particulate matter exposure aggravates osteoarthritis severity.

Several diseases have been linked to particulate matter (PM) exposure. Outdoor activities, such as road running or jogging, are popular aerobic exercises due to few participatory limitations. Osteoarthritis (OA) is a progressive degenerative joint disease, usually observed at age 40, and not noticed before pain or diagnosis. Although exercise has health benefits, it is unclear whether outdoor jogging in higher PM (standard reference material 1649b, SRM 1649b) concentration environments could affect OA development or severity. Hence, a PM exposure monosodium iodoacetate (MIA)-induced OA animal jogged model was established for investigation. Results showed that high doses of PM (5 mg) significantly increased pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6, and M1 macrophages in the lung region, also obtained in systemic IL-6 and TNF-α expressions in this MIA-OA rat model. Moreover, levels of osteocalcin, cartilage oligomeric matrix protein (COMP), and N-telopeptides of type I collagen were especially influenced in MIA+PM groups. Morphological and structural changes of the knee joint were detected by micro-computed tomography images (micro-CT) and immunohistochemistry. MIA + PM rats exhibited severe bone density decrease, cartilage wear, and structure damages, accompanied by lower levels of physical activity, than the sham group and groups receiving MIA or PM alone. The findings suggest that the severity of OA could be promoted by PM exposure with a PM concentration effect via systemic inflammatory mechanisms. To the best of our knowledge, this is the first study to provide direct effects of PM exposure on OA severity.

Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip and Knee Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease driven by a blend of inflammatory and biomechanical processes. Studies using human samples to understand inflammatory mechanisms in OA frequently recruit OA patients with different affected joints, even though recent evidence indicates that OA is a heterogeneous disease which only culminates in a common end point. Differences in age of onset and the dynamics of disease progression suggest that different joints may represent different disease entities, thereby diluting the discovery potential in a combined analysis. We hypothesized that different OA joints may also differ in immunopathology within the synovium. To investigate this hypothesis, we profiled the immune cell contribution (flow cytometry) and cytokine release profiles (ELISA) in purified synovial membrane mononuclear cells from 50 patients undergoing either hip (n = 34) or knee (n = 16) replacement surgery. Unsupervised computational approaches were used for disease deconstruction. We found that hip and knee osteoarthritis are not identical in respect to the inflammatory processes that take place in the synovial membrane. Instead, we report that principally CD14+ macrophages are expanded fourfold in the synovial membrane of patients with knee OA compared to hip OA, with a trend to higher expression in CD8+ T cells, while CD4+ T cells, B cells, and NK cells were found at comparable quantities. Upon isolation and culture of cells from synovial membrane, isolates from hip OA released higher concentrations of Eotaxin (CCL11), G-CSF, GM-CSF, INF-γ, IP-10 (CXCL10), TNF-α, MIP-1α (CCL3), MIP-1β (CCL4), IL-4, IL-10, IL-17, and lower concentrations of stem cell factor (SCF), thereby highlighting the difference in the nature of hip and knee osteoarthritis. Taken together, this study establishes hip and knee OA as immunologically distinct types of OA, and creates a resource of the cytokine expression landscape and mononuclear cell infiltration pattern of patients with hip and knee osteoarthritis.

Comparative clinical and cost analysis between surgical and non-surgical intervention for knee osteoarthritis

ObjectiveTo evaluate the management and costs of osteoarthritis of the knee (OAK), a progressive joint disease due to bone and cartilage degeneration, with significant personal and societal impact.MethodsWe prospectively analyzed the clinical outcomes and quantifiable cumulative direct costs of patients with OAK referred to our multidisciplinary OA program over a two year time period. One hundred thirty-one subjects were assessed. All demonstrated radiographic criteria for moderate to severe OAK. Western Ontario McMaster Osteoarthritis Index (WOMAC), Minimal Clinically Important Improvement (MCII), and change in BMI were recorded and analyzed. Total medical and surgical direct costs for all subjects during the two year time period were determined.ResultsFive patients underwent total joint replacement during the two years of study. Among the group as a whole, a significant overall improvement in WOMAC scores was noted at the two year time point follow-up. After dividing the group into tertiles by baseline WOMAC scores, 46% achieved MCII. Significant weight loss was noted for individuals with baseline BMI of > 30. As all patients were considered “de facto” surgical candidates at referral, an average net savings of $9551.10 of direct costs per patient, or a potential total of $1,203,438.60 for the entire group, could be inferred as a result of medical as opposed to surgical management.ConclusionThese findings support the benefits of multidisciplinary medical management for patients with significant OAK. This approach is clinically beneficial and may provide significant cost savings. Such models of care can substantially improve the long-term outcome of this highly prevalent condition and reduce societal and financial burdens.

Skeletal Changes Associated with Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disorder in which progressive articular cartilage loss occurs alongside pathological changes in subchondral bone and other joint tissues. The pathophysiological role of bone in OA has been a point of interest for many years and has resurfaced again in recent years as a potential target for new treatments. Articular cartilage and subchondral bone together form the osteochondral unit. Its homeostasis and integrity are reliant on biochemical crosstalk and biomechanical interplay between the two. Subchondral bone, with its relatively greater stiffness and strength, provides mechanical support to the overlying cartilage and absorbs much of the mechanical force transmitted through the joint. Mechanical instability in osteoarthritic joints is thought to be a significant risk-factor in joint disease, due to the mechano-sensitive nature of many of its native tissues. Although the progression of joint disease remains incompletely understood, significant changes in subchondral bone remodelling, structure, composition, and mechanical properties have been documented in animal and human studies of OA. The purpose of this review is to explore and discuss these bony changes associated with disease and, in particular, contextualise the basic science and clinical literature on the role of subchondral bone in OA.

Multiple sclerosis neuropathic arthropathy of elbow: Report of a rare case and literature review

Neuropathic arthropathy (NA) is a progressive degenerative and destructive joint disease associated with underlying chronic neurologic deficit. A 34-year-old woman was referred to our tumor clinic with swelling and destruction of her left elbow joint. Except for a 5-year history of multiple sclerosis (MS), she had no other underlying diseases. Suspected of tumor involvement, she had been undergone an open biopsy. The pathologic report was fibromatosis, which was not compatible with imaging studies and clinical presentations. Second surgical inspection and cellular study didn’t prove tumoral involvement. Magnetic resonance images (MRIs) showed multiple hyper signal plaques in her cervical spine. MRI findings, clinical features, surgical observations, and disproportionate painless elbow destruction all confirmed the MS NA diagnosis.

Osteoarthritis biomarker responses and cartilage adaptation to exercise: A review of animal and human models.

Regular physical activity has been suggested as having both preventive and therapeutic benefits for individuals with osteoarthritis (OA). However, evidence of whether exercise and which type of exercise constitutes a benefit or a risk in the development and progression of OA remains debatable. This may be due to the evaluation of the effect of physical activity or new disease-modifying OA drugs which is currently based on radiographic criteria (eg, joint space width) and the lack of correlation with clinical signs and symptoms (eg, pain and loss of function). Moreover, OA typically manifests itself as changes within the joint space and subchondral bone as well as the whole joint structure, including progressive degradation of cartilage, menisci, ligaments, and synovial inflammation. Biomarkers are being developed to quantify joint remodeling and disease progression notably involving the articular cartilage and synovial fluid. The primary purpose of this review was to evaluate the current literature and to provide further insight based on OA biomarkers and the role physical activity plays in the management of OA. Osteoarthritis biomarkers together with radiographic imaging evidence will ideally guide healthcare providers to incorporate exercise recommendations into clinical management and offer patients evidence-based and individually tailored exercise prescriptions.

Development and validation of a novel high performance liquid chromatography-coupled with Corona charged aerosol detector method for quantification of glucosamine in dietary supplements.

IntroductionGlucosamine dietary supplements are commonly used for the management of osteoarthritis (OA). However, clinical trials have reported varying outcomes with regard to joint function and disease progression. One of the possible reasons for variability in observed effects of glucosamine could be that, unlike prescription drugs, the quality of manufactured dietary supplements is not closely monitored in many countries. Therefore, there is the possibility that the actual amount of glucosamine present in a dietary supplement is different from that claimed on the label. The quality control of glucosamine supplements is further complicated by the unavailability of a simple and effective analytical method for the analysis of glucosamine. Therefore, the aim of this study was to develop a simple analytical method that could be easily adapted by the pharmaceutical industry for routine analysis of glucosamine.AimsTo develop a novel high-performance liquid chromatography (HPLC) method for the quantification of glucosamine, and determine the amount of glucosamine present in a sample of dietary supplements commercially available in Australia and India.MethodsChromatographic separation of glucosamine was achieved using a zwitter-ionic hydrophilic interaction liquid chromatography column with a mobile phase consisting of 60% acetonitrile and 40% of 85 mM ammonium acetate, at a flow rate of 0.3 mL/min and column temperature 40°C. The developed method was validated for intra- and inter-day linearity, accuracy, precision, and reproducibility. The newly-developed method was subsequently used to analyse 12 glucosamine supplements.ResultsThe developed method was selective for glucosamine, which had a retention time of 5.9 min. The standard curve was linear with a correlation coefficient (r2) exceeding 0.99, over the range of 10–200 μg/mL for glucosamine. The relative standard deviations for intra- and inter-day accuracy, precision and reproducibility were all less than 4%. The amount of glucosamine determined in six Australian and six Indian glucosamine supplements ranged between 98.7–101.7% and 85.9–101.8% of the labelled values, respectively.DiscussionUnlike previous HPLC methods, this newly-developed HPLC technique does not require pre-derivatisation and can separate glucosamine from both hydrochloride and sulphate salts, and from other amino sugars, such as chondroitin sulphate present in dietary supplements. This simple and effective technique can be employed by analytical laboratories for the quality control of glucosamine dietary supplements.ConclusionThe current study has developed a new analytical technique using HPLC-Corona CAD, which can analyse underivatised glucosamine hydrochloride and sulphate within 6 minutes. Using the novel assay, we confirmed that unlike the tested Australian dietary supplements, only half of the tested Indian products had a glucosamine content within ±10% of what was claimed on the label.

The Protective Effect of Magnolol in Osteoarthritis: In vitro and in vivo Studies.

Osteoarthritis (OA), defined as a long-term progressive joint disease, is characterized by cartilage impairment and erosion. In recent decades, magnolol, as a type of lignin extracted from Magnolia officinalis, has been proved to play a potent anti-inflammatory role in various diseases. The current research sought to examine the latent mechanism of magnolol and its protective role in alleviating the progress of OA in vivo as well as in vitro experimentations. In vitro, the over-production of Nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), induced by interleukin-1 beta (IL-1β), were all inhibited notably by magnolol in a concentration-dependent manner. Moreover, magnolol could also downregulate the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5). All these changes ultimately led to the deterioration of the extracellular matrix (ECM) induced by IL-1β. Mechanistically, magnolol suppressed the activation of PI3K/Akt/NF-κB pathway. Furthermore, a powerful binding capacity between magnolol and PI3K was also revealed in our molecular docking research. In addition, magnolol-induced protective effects in OA development were also detected in a mouse model. In summary, this research suggested that magnolol possessed a new therapeutic potential for the development of OA.

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

Attenuation of surgically-induced osteoarthritis (OA) by inhibition of autotaxin

Purpose: Osteoarthritis (OA) is a chronic, progressive joint disease leading to a poor quality of life. Previously, we have reported that selected Lysophoshatidylcholines (lysoPCs) are increased in animal models of OA (Datta et al., 2017, PMID: 28811491). We also identified that these particular metabolites may promote OA pathogenesis in an autotaxin (ATX) - dependent manner. ATX is an enzyme responsible for the conversion of lysoPC to the inflammatory mediator lysophosphatidic acid (LPA). Previous studies have also shown that ATX levels in plasma and synovial fluid correlate with the severity of knee osteoarthritis (Mabey et al., 2015, PMID: 25659292). Thus, we sought to identify if local pharmacological inhibition of ATX can attenuate surgically-induced OA in vivo and its mechanism of action in vitro. Methods: Nine week-old mice were subjected to surgically-induced OA by destabilizing medial meniscus (DMM surgery). ATX antagonist (PF -8380, Pfizer) was injected intra-articularly in the mouse knee joints at 2nd,4th 6th and 8th week of post surgery. Subsequent knee joints were collected at 10 weeks of post surgery and histopathological changes were evaluated. Primary human chondrocytes were treated with IL-1β/ATX antagonist, and the expression of catabolic markers were determined. Results: Local injection of ATX antagonist reduced the degree of cartilage degeneration in surgically induced OA models compared to saline injected controls. ATX antagonist also reduced the amount of synovitis as compared to controls. Immunohistochemical analysis of mouse knee joints showed decreased expression of catabolic markers (C1-2C and MMP 13) in ATX treated mice compared to control mice. In vitro, ATX antagonist attenuated IL-1β-induced increases in the expression of MMP13 Conclusions: Inhibition of ATX attenuates surgically-induced OA. We are currently investigating the mechanism of action of ATX in attenuating OA. Our data, to date, suggests pre-clinical efficacy of ATX to limit OA progression.

Association between vitamin d status and mineralization disorder of osteophyte in middle aged and elderly population with kellgren-lawrence grade 2 of knee osteoarthritis-a sportology core study 2

Purpose: Osteoarthritis of the knee (knee OA) is a slowly progressive joint disease and a leading cause of impaired mobility in the elderly. Osteophyte formation has been considered to be a secondary phenomenon of the pathogenesis of knee OA. However, particular attention has been paid to osteophytes, as it has been revealed to have distinct and unique roles in the process of OA pathogenesis. Osteophytes develop at the peripheries of the articular cartilage by following the processes of the endochondral ossification. Histologically, osteophytes are composed of the cartilage and bone parts. Because of the limitation in detectability of the cartilage part of osteophytes by radiography or conventional magnetic resonance imaging (MRI), we have reported that the cartilage part of osteophytes can be detected by using T2 mapping MRI (Arthritis Res Ther, 19:201, 2017). It has been recently recognized that vitamin D insufficiency and deficiency are common in the elderly. Vitamin D plays an important role for bone formation and mineralization. While vitamin D status has been speculated to affect the pathophysiology of knee OA, it is still controversial whether or how vitamin D status is involved in the pathophysiology of knee OA. The aim of this study was to examine whether there was any association between vitamin D status and osteophytes morphology, especially bone and cartilage part of osteophyte, in patients with early stage knee OA. Methods: 643 subjects [349 (54.3%) female patients] who had participated the cohort study of our university with early stage medial knee OA diagnosed in X-ray examination classified grade 2 of Kellgren-Lawrence (KL) classification were enrolled in the present study. Blood samples of the subjects were taken. Serum 25-hydroxy vitamin D [s25(OH)D] level was assessed by ELISA method. The <20 ng/ml of s25(OH)D level was considered to be vitamin D deficiency, while ≥20 ng/ml and <25 ng/ml or ≥25 ng/ml of s25(OH)D level was considered to be vitamin D insufficiency or sufficiency, respectively. The clinical manifestations were evaluated by the Japanese Knee Osteoarthritis Measure (JKOM) score, which is a patient-based, self-answered evaluation score that includes 4 subcategories (J Rheumatol, 2005). Locomotive syndrome risk test, and lumbar spine bone mineral density (LS-BMD) were examined. All subjects examined T2 mapping MRI on their left knee joint using 3T MRI system. We evaluated osteophytes length by T2 mapping MRI, which enable us to detect cartilage- (cartilage OP) and bone-parts of osteophyte (bone OP), separately, as reported previously (Arthritis Res Ther, 19:201, 2017). All subjects were divided into two groups according to their s25(OH)D levels; the vitamin D deficiency group: s25(OH)D <20 ng/ml and the vitamin D insufficiency or sufficiency group: s25(OH)D≧20 ng/ml. Correlation of s25(OH)D levels and each parameter were analyzed by using t-test. A liner regression analysis was conducted to examine the associations between s25(OH)D and variables examined. A p-value less than 5% was considered to be statistically significant. All analyses were undertaken using the statistical package SPSS. Results: The age and s25(OH)D level of the subjects was 72.7 (SD 5.4) years old and 21.4 (SD 6.5) ng/ml,respectively, on average. Two hundred and eighty-four subjects (44%) were classified as the vitamin D deficiency group, while remaining 360 subjects (56%) were classified as the vitamin D insufficiency or sufficiency group. Mean serum calcium (adjusted for the serum albumin level, if it was 4.0 g/dl or less), phosphorus and BAP levels of the subjects were within the reference range. No one was diagnosed with osteomalacia. Total osteophyte length of the vitamin D insufficiency or sufficiency group (4.30 mm) was significantly longer in comparison to that of the vitamin D deficiency group (3.95 mm, p=0.005). There was no significant difference of cartilage part of osteophyte between two groups. On the other hand, the bone part osteophyte of the deficiency group (1.86 mm) was significantly shorter than that of the insufficiency or sufficiency group (2.08 mm, p=0.01). In addition, s25(OH)D levels of the subjects were correlated with MME (p=0.02), Skeletal Muscle Mass (SMM) (p=0.0006), Two step test (p=0.003) in Locomotive risk test, and LS-BMD(p=0.001). Conclusions: Almost half of the middle aged and elderly subjects among the population cohort with early stage knee OA changes was vitamin D deficiency and was suggested to have mineralization disorder of osteophyte formation in this condition.

A Novel Cartilage Fragments Stimulation Model Revealed that Macrophage Inflammatory Response Causes an Upregulation of Catabolic Factors of Chondrocytes In Vitro.

Osteoarthritis is a progressive joint disease characterized by cartilage degradation and synovial inflammation. Presence of cartilage fragments in the joint due to degradation of cartilage is thought to be associated with local inflammatory response and progressive osteoarthritic process. Understanding the mechanism by which cartilage fragments elicit this destructive process should aid in designing novel therapeutic approaches. Therefore, objective of current study is to establish an in vitro model to examine the cross-talk between chondrocytes and cartilage fragments-stimulated macrophages. Cartilage fragments were prepared from femoral head cartilages of mice and analyzed using a scanning electron microscope and particle size analyzer. Bone marrow-derived macrophages were co-cultured with cartilage fragments and chondrocytes using transwell co-culture system. Macrophage inflammatory mediators in supernatant of cultures were determined by ELISA and gene expression of macrophages and chondrocyte were quantified by qRT-PCR. Shapes of cartilage fragments were irregular with sizes ranged between 0.54 and 55 μm. Macrophages cultured with cartilage fragments released significantly higher concentrations of TNF-α, IL-6, and NO than those of mock and control. Consistently, gene expressions of TNF-α, IL-6, and MMP-9 were significantly increased in stimulated macrophages. The elevation in production of pro-inflammatory molecules in stimulated macrophages cultures were coincident with an increase in gene expression of chondrocyte MMP-13, iNOS, and IL-6. We developed an in vitro co-culture model to study the impact of stimulation of macrophage by cartilage fragments on the expression of chondrocyte carbolic factors. Our results revealed that cartilage fragments triggered macrophages inflammatory response that enhanced the production of chondrocyte catabolic factors.