Novel hyaluronic acid–methotrexate conjugates for osteoarthritis treatment

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA–MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA–MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.     

Determination of the number of degrees of freedom of the trapeziometacarpal joint–An in vitro study

ObjectiveMost of the studies about trapeziometacarpal joint assume that it exhibits only two independent degrees of freedom, but the experimental or theoretical support for considering a two-degrees of freedom model is not always clear.Materials and methodsTherefore, an in vitro kinematic study has been designed to demonstrate, from experimental data, that only two of the trapeziometacarpal degrees of freedom (i.e., flexion/extension and adduction/abduction) are non-null and independent. Several movements of maximal amplitude in flexion, abduction and circumduction have been realized and the relative position and orientation of the segment coordinate system embedded on the first metacarpal with respect to that embedded on the trapezium have been collected using electromagnetic sensors. The trapeziometacarpal rotations have been described using a joint coordinate system and the joint displacements have been evaluated on the axes of this coordinate system.ResultsThe root mean square (RMS) values of the joint displacement components have been found small enough to assume that the trapeziometacarpal joint has no translation degrees of freedom. A paraboloid coupling equation has been found between the internal/external rotation angle and the two other, flexion/extension and adduction/abduction, angles.ConclusionThus, this study demonstrates that the trapeziometacarpal joint has only two independent rotational degrees of freedom, and further, the described methodology could also be used to determine the coupling laws between degrees of freedom of various joints.     

甲状腺相关性眼病的研究及治疗进展

甲状腺相关性眼病(TAO)是具有一系列体征和症状的多因素自身免疫性疾病。糖胺聚糖(GAG)的过量沉积、炎性浸润以及细胞因子的过度产生是甲状腺相关性眼病的主要特征。甲状腺相关性眼病的临床表现多种多样,可以从轻度的眼睑肿胀、上睑退缩、结膜充血、眼球突出乃至重度的威胁视力的暴露性角膜溃疡和压迫性视神经病变。通常,根据病史和查体是可以直接诊断甲状腺相关性眼病。实验室检查和影像学检查对于诊断甲状腺相关性眼病也具有一定的作用。目前可以根据"NO SPECS"法、临床活动评分(CAS)和VISA分类这三种方法对TAO病情情况进行分类。甲状腺相关性眼部的治疗包括保守治疗、药物治疗、眼眶放射治疗和手术治疗等,需根据患者的病情来决定其治疗方案。本文的目的是帮助眼科医生了解甲状腺相关性眼病的分期(轻度,中度至重度和视力威胁)的重要性和相关的可用治疗方式。     

The validity and heritability of self-report osteoarthritis in an Australian older twin sample.

In order to investigate the genetic and environmental antecedents of osteoarthritis (OA), self-report measures of joint pain, stiffness and swelling were obtained from a population-based sample of 1242 twin pairs over 50 years of age. In order to provide validation for these self-report measures, a subsample of 118 twin pairs were examined according to the American College of Rheumatology clinical and radiographic criteria for the classification of osteoarthritis. A variety of statistical methods were employed to identify the model derived from self-report variables which would provide optimal prediction of these standardised assessments, and structural equation modelling was used to determine the relative influences of genetic and environmental influences on the development of osteoarthritis. Significant genetic effects were found to contribute to osteoarthritis of the hands, hips and knees in women, with heritability estimates ranging from 30-46% depending on the site. In addition, the additive genetic effects contributing to osteoarthritis in various parts of the body were confirmed to be the same. Statistically significant familial aggregation of osteoarthritis in men was also observed, but it was not possible to determine whether this was due to genetic or shared environmental effects.     

Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice

Introduction  

Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet.     

Stem cell application for osteoarthritis in the knee joint: A minireview

Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.     

Oral leiomyosarcoma in childhood. Report of a case with fine needle aspiration cytology

BACKGROUND: Leiomyosarcomas are rare tumors in the pediatric age group, and occurrence of this neoplasm in the oral cavity is exceedingly rare. This article highlights the fine needle aspiration (FNA) cytology diagnosis of a case of recurrent oral leiomyosarcoma in childhood. CASE: An 11-year-old male noticed a swelling in the oral cavity near the left lower jaw. It was excised and diagnosed as leiomyosarcoma on histopathology. Four months later the patient presented with a progressive swelling in the oral cavity that extended to the lower jaw. The recurrent swelling was subjected to FNA, and its cytologic features were consistent with leiomyosarcoma. There was a very good initial response to chemotherapy and radiation therapy. However, because of noncompliance with advice for further therapy, the patient had a second local recurrence and dissemination of the disease to the skeletal system, abdomen and thorax. FNA cytology diagnosis of the second locally recurrent lesion and abdominal mass were consistent with leiomyosarcoma. Immunocytochemical staining revealed a positive reaction in the cytoplasm of tumor cells for vimentin and desmin in the FNA smear and paraffin section, respectively. CONCLUSION: Fine needle aspiration cytology is a useful technique for detection of recurrence and metastasis during follow-up of childhood oral leiomyosarcoma.     

Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – A randomized double blind placebo controlled trial

Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (guggulu) has been known. It posses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double blind placebo controlled crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.     

Osteoarthritis subpopulations and implications for clinical trial design

Treatment guidelines for osteoarthritis have stressed the need for research on clinical predictors of response to different treatments. However, identifying such clinical predictors of response is less easy than it seems, and there is not a given classification of osteoarthritis subpopulations. This review article highlights the key methodical issues when analyzing and designing clinical studies to detect important subgroups with respect to treatment effect. In addition, we discuss the main osteoarthritis subpopulations and give examples of how specific treatment effects in these subpopulations have been assessed.     

Treatment with recombinant interferon-beta reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis

We investigated the therapeutic potential and mechanism of action of IFN-beta protein for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections of recombinant mouse IFN-beta or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-kappaB ligand, and c-Fos was evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-beta. We also examined the effect of IFN-beta on NF-kappaB activity. IFN-beta, at 0.25 microg/injection and higher, significantly reduced disease severity in two experiments, each using 8-10 mice per treatment group. IFN-beta-treated animals displayed significantly less cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required for osteoclastogenesis, receptor activator of NF-kappaB ligand and c-Fos. Tumor necrosis factor alpha and IL-6 expression were significantly reduced, while IL-10 production was increased after IFN-beta treatment. IFN-beta reduced expression of IL-6, IL-8, and GM-CSF in RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-kappaB activity. The data support the view that IFN-beta is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation.     

Extraction of mechanical properties of articular cartilage from osmotic swelling behavior monitored using high frequency ultrasound

Articular cartilage is a biological weight-bearing tissue covering the bony ends of articulating joints. Negatively charged proteoglycan (PG) in articular cartilage is one of the main factors that govern its compressive mechanical behavior and swelling phenomenon. PG is nonuniformly distributed throughout the depth direction, and its amount or distribution may change in the degenerated articular cartilage such as osteoarthritis. In this paper, we used a 50 MHz ultrasound system to study the depth-dependent strain of articular cartilage under the osmotic loading induced by the decrease of the bathing saline concentration. The swelling-induced strains under the osmotic loading were used to determine the layered material properties of articular cartilage based on a triphasic model of the free-swelling. Fourteen cylindrical cartilage-bone samples prepared from fresh normal bovine patellae were tested in situ in this study. A layered triphasic model was proposed to describe the depth distribution of the swelling strain for the cartilage and to determine its aggregate modulus H(a) at two different layers, within which H(a) was assumed to be linearly dependent on the depth. The results showed that H(a) was 3.0+/-3.2, 7.0+/-7.4, 24.5+/-11.1 MPa at the cartilage surface, layer interface, and deep region, respectively. They are significantly different (p<0.01). The layer interface located at 70%+/-20% of the overall thickness from the uncalcified-calcified cartilage interface. Parametric analysis demonstrated that the depth-dependent distribution of the water fraction had a significant effect on the modeling results but not the fixed charge density. This study showed that high-frequency ultrasound measurement together with triphasic modeling is practical for quantifying the layered mechanical properties of articular cartilage nondestructively and has the potential for providing useful information for the detection of the early signs of osteoarthritis.     

Pathological mechanism of chondrocytes and the surrounding environment during osteoarthritis of temporomandibular joint

Temporomandibular joint (TMJ) osteoarthritis is a common chronic degenerative disease of the TMJ. In order to explore its aetiology and pathological mechanism, many animal models and cell models have been constructed to simulate the pathological process of TMJ osteoarthritis. The main pathological features of TMJ osteoarthritis include chondrocyte death, extracellular matrix (ECM) degradation and subchondral bone remodelling. Chondrocyte apoptosis accelerates the destruction of cartilage. However, autophagy has a protective effect on condylar chondrocytes. Degradation of ECM not only changes the properties of cartilage but also affects the phenotype of chondrocytes. The loss of subchondral bone in the early stages of TMJ osteoarthritis plays an aetiological role in the onset of osteoarthritis. In recent years, increasing evidence has suggested that chondrocyte hypertrophy and endochondral angiogenesis promote TMJ osteoarthritis. Hypertrophic chondrocytes secrete many factors that promote cartilage degeneration. These chondrocytes can further differentiate into osteoblasts and osteocytes and accelerate cartilage ossification. Intrachondral angiogenesis and neoneurogenesis are considered to be important triggers of arthralgia in TMJ osteoarthritis. Many molecular signalling pathways in endochondral osteogenesis are responsible for TMJ osteoarthritis. These latest discoveries in TMJ osteoarthritis have further enhanced the understanding of this disease and contributed to the development of molecular therapies. This paper summarizes recent cognition on the pathogenesis of TMJ osteoarthritis, focusing on the role of chondrocyte hypertrophy degeneration and cartilage angiogenesis.     

Developments in the clinical understanding of osteoarthritis

With the recognition that osteoarthritis is a disease of the whole joint, attention has focused increasingly on features in the joint environment which cause ongoing joint damage and are likely sources of pain. This article reviews current ways of assessing osteoarthritis progression and what factors potentiate it, structural abnormalities that probably produce pain, new understandings of the genetics of osteoarthritis, and evaluations of new and old treatments.     

Gene therapy for osteoarticular disorders

Osteoarticular disorders are the major cause of disability in Europe and North America. It is estimated that rheumatoid arthritis affects 1 % of the population and that more than two third of people over age 55 develop osteoarthritis. Because there are no satisfactory treatments, gene therapy offers a new therapeutic approach. The delivery of cDNA encoding anti-arthritic proteins to articular cells has shown therapeutic efficacy in numerous animal models in vivo. Through the development and the experimental progresses that have been made for both rheumatoid arthritis and osteoarthritis, this review discusses the different gene therapy strategies available today and the safety issues with which they may be associated. Among the different vectors available today, adeno-associated virus seems the best candidate for a direct in vivo gene delivery approach for the treatment of joint disorders.     

Tissue engineering through autologous mesenchymal stem cells

The regeneration of damaged cartilage in different pathological situations is a major goal for the future and could be achieved through cell and/or gene therapy. Mesenchymal stem cells (MSCs) are the progenitors of multiple lineages, including bone, cartilage, muscle, fat, and astrocytes. MSCs seem to be the best candidates for cell therapy to regenerate injured tissue, as they are easily isolated from bone marrow and can be rapidly amplified. Full healing is extremely demanding, however, and includes integration of the regenerated tissue within the surrounding host tissue and true differentiation through pathways involved in embryonic development. This goal might be reached through the combined use of scaffolds, MSC-mediated therapy and the expression of selective differentiating factors. The long-term behavior of MSCs associated with biomaterials and implanted in pathological joints remains to be investigated before clinical application in osteoarthritis or rheumatoid arthritis.     

A combination of methods for the preparation of highly intact mitoplasts from beef heart mitochondria

Beef heart mitochondria are noted for difficulty of fractionation compared to mitochondria from other tissues. A method that would give the desired efficiency while leaving the inner membrane intact did not seem to be available. Four variables, alone and in all possible combinations, were evaluated for their effectiveness in fractionation. These variables were treatment with digitonin, hypotonic swelling, phospholipase A2 predigestion, and addition of high concentrations of EDTA. The efficiency of fractionation was evaluated by electron microscopy and marker enzyme assays. Highly intact mitoplasts were obtained when the mitochondria were treated with digitonin together with intense hypotonic swelling, or moderate hypotonic swelling and phospholipase A2 predigestion, or EDTA addition and phospholipase predigestion. The enzyme GTP:AMP phosphotransferase was found to be located exclusively in the matrix compartment.     

Robusticity and osteoarthritis at the trapeziometacarpal joint in a Bronze Age population from Tell Abraq, United Arab Emirates

Osteoarthritis (OA) is a progressive disease of the joints and can cause pain, reduced range of motion and strength, and ultimately loss of function at affected joints. Osteoarthritis often occurs at sites where biomechanical stress is acutely severe or moderate but habitual over the course of a lifetime. Skeletal remains from an Umm an-Nar tomb at Tell Abraq, United Arab Emirates (ca. 2300 BC), were recovered and represented over 300 individuals of all ages. The remains were disarticulated, commingled, and mostly fragmented. An analysis of 650 well-preserved adult metacarpal and carpal bones, from the tomb's western chamber, revealed that over 53% of the trapeziometacarpal joint facets showed signs of OA varying from mild to severe. The first and second metacarpals and trapezium bones were sided and evaluated for OA at the trapeziometacarpal joint articulations. Osteoarthritis was detected on 53% of the first metacarpals, 40% of the second metacarpals, and 57% of the trapezium bones. All specimens appeared enlarged, and the first metacarpals were assessed for sexual identification and robusticity. Eighty-five percent of the bones were probable males, and more than 80% of them had a robusticity index of 60 or higher. A strong correlation was found between OA, sex, and robusticity. High levels of OA and robusticity at the thumb suggest that the people of Tell Abraq were habitually involved in biomechanically challenging work with their hands.     

Green tea: a new option for the prevention or control of osteoarthritis

IL-1β is a major cytokine driving the inflammatory processes leading to the pathophysiology of osteoarthritis and other inflammatory diseases. Blockade of IL-1β activity using substances such as the naturally occurring IL-1 receptor antagonist or anti-IL-1β monoclonal antibody are currently being used or tested as therapy. However, such treatments are ineffective in osteoarthritis. In a recent study, epigallocatechin-3-gallate, a green tea polyphenol, was found to be effective in reducing IL-1β-induced inflammatory cytokines, TNFα, IL-6, granulocyte-macrophage colony-stimulating factor and several chemokines from human chondrocytes. The use of green tea polyphenols may be beneficial as a therapeutic addition to biologics that control IL-1β activity by increasing effectiveness and/or reducing dosage.     

High-resolution measurements of the multilayer ultra-structure of articular cartilage and their translational potential

Current musculoskeletal imaging techniques usually target the macro-morphology of articular cartilage or use histological analysis. These techniques are able to reveal advanced osteoarthritic changes in articular cartilage but fail to give detailed information to distinguish early osteoarthritis from healthy cartilage, and this necessitates high-resolution imaging techniques measuring cells and the extracellular matrix within the multilayer structure of articular cartilage. This review provides a comprehensive exploration of the cellular components and extracellular matrix of articular cartilage as well as high-resolution imaging techniques, including magnetic resonance image, electron microscopy, confocal laser scanning microscopy, second harmonic generation microscopy, and laser scanning confocal arthroscopy, in the measurement of multilayer ultra-structures of articular cartilage. This review also provides an overview for micro-structural analysis of the main components of normal or osteoarthritic cartilage and discusses the potential and challenges associated with developing non-invasive high-resolution imaging techniques for both research and clinical diagnosis of early to late osteoarthritis.