Development Of Joint Disease Research Articles

Targeting CD44 Receptor Pathways in Degenerative Joint Diseases: Involvement of Proteoglycan-4 (PRG4).

Rheumatoid arthritis (RA), osteoarthritis (OA), and gout are the most prevalent degenerative joint diseases (DJDs). The pathogenesis underlying joint disease in DJDs remains unclear. Considering the severe toxicities reported with anti-inflammatory and disease-modifying agents, there is a clear need to develop new treatments that are specific in their effect while not being associated with significant toxicities. A key feature in the development of joint disease is the overexpression of adhesion molecules, e.g., CD44. Expression of CD44 and its variants in the synovial tissues of patients with DJDs is strongly associated with cartilage damage and appears to be a predicting factor of synovial inflammation in DJDs. Targeting CD44 and its downstream signaling proteins has emerged as a promising therapeutic strategy. PRG4 is a mucinous glycoprotein that binds to the CD44 receptor and is physiologically involved in joint lubrication. PRG4-CD44 is a pivotal regulator of synovial lining cell hemostasis in the joint, where lack of PRG4 expression triggers chronic inflammation and fibrosis, driven by persistent activation of synovial cells. In view of the significance of CD44 in DJD pathogenesis and the potential biological role for PRG4, this review aims to summarize the involvement of PRG4-CD44 signaling in controlling synovitis, synovial hypertrophy, and tissue fibrosis in DJDs.

Sex Disparities of the Sacroiliac Joint: Focus on Joint Anatomy and Imaging Appearance.

The sacroiliac joint (SIJ) is an anatomically complex joint which, as a functional unit with the pelvis and spine, is of decisive biomechanical importance for the human body. It is also a commonly overlooked source of lower back pain. Like the entire bony pelvis, the SIJ exhibits major sexual dimorphisms; thus, the sex-dependent evaluation of this joint is becoming increasingly important in clinical practice, both anatomically with joint shape variations and biomechanical differences as well as in terms of image appearance. The influence of the SIJ shape, which differs in women and men, is crucial for the different biomechanical joint properties. These differences are important in the development of joint diseases at the SIJ, which shows a specific difference between the sexes. This article aims to provide an overview of sex disparities of the SIJ regarding different anatomical and imaging appearances to further understand the insights into the interplay of sex differences and SIJ disease.

Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes - Then and Now.

Cartilages are unique in the family of connective tissues in that they contain a high concentration of the glycosaminoglycans, chondroitin sulfate and keratan sulfate attached to the core protein of the proteoglycan, aggrecan. Multiple aggrecan molecules are organized in the extracellular matrix via a domain-specific molecular interaction with hyaluronan and a link protein, and these high molecular weight aggregates are immobilized within the collagen and glycoprotein network. The high negative charge density of glycosaminoglycans provides hydrophilicity, high osmotic swelling pressure and conformational flexibility, which together function to absorb fluctuations in biomechanical stresses on cartilageduring movement of an articular joint. We have summarized information on the history and current knowledge obtained by biochemical and genetic approaches, on cell-mediated regulation of aggrecan metabolism and its role in skeletal development, growth as well as duringthe development of joint disease. In addition, we describe the pathways for hyaluronan metabolism, with particular focus on the role as a "metabolic rheostat" during chondrocyte responses in cartilage remodeling in growth and disease.Future advances in effective therapeutic targeting of cartilage loss during osteoarthriticdiseases of the joint as an organ as well as in cartilage tissue engineering would benefit from 'big data' approaches and bioinformatics, to uncover novel feed-forward and feed-back mechanisms for regulating transcription and translation of genes and their integration into cell-specific pathways.

TGF-β2 increases cell-cell communication in chondrocytes via p-Smad3 signalling

Connexin 43 (Cx43)-mediated gap junction intercellular communication (GJIC) plays a crucial role in the pathology and physiology of joint tissues. Transforming growth factor-β2 (TGF-β2), one of the potent regulatory factors in chondrocytes, plays a key role in the regulation of cell cycle and development of joint diseases. However, it is still unknown how TGF-β2 mediates GJIC in chondrocytes. The aim of this study was to explore the potential mechanism by which TGF-β2 regulates GJIC in chondrocytes. CCK-8 assays and scratch assays were performed to define the role of TGF-β2 on cell proliferation and migration. The scrape loading/dye transfer assay and scanning electron microscopy (SEM) were used to verify the effect of TGF-β2 on GJIC between chondrocytes. qPCR was performed to analyse the expression of genes in the gap junction protein family in chondrocytes. The expression of the Cx43 protein and phosphorylated Smad3 (p-Smad3) was evaluated by western blot assay. Immunofluorescence staining was used to explore p-Smad3 signalling pathway activation and Cx43 distribution. From these experiments, we found that the Cx43 protein was the most highly expressed member of the gap junction protein family in chondrocytes. We also found that TGF-β2 facilitated cell-to-cell communication in chondrocytes by upregulating Cx43 expression in chondrocytes. Finally, we found that TGF-β2 activated Smad3 signalling and promoted the nuclear aggregation of p-Smad3. Inhibition experiments by SIS3 also confirmed that TGF-β2-mediated GJIC through p-Smad3 signalling. For the first time, this study confirmed that TGF-β2 could regulate the formation of Cx43-mediated GJIC in chondrocytes via the canonical p-Smad3 signalling pathway.

Impact of Cadmium Mediated by Tobacco Use in Musculoskeletal Diseases.

Tobacco use has a negative impact on health due to its relationship with the development of high-mortality diseases, such as pulmonary cancer. However, the effect of cadmium (Cd), present in tobacco smoke, on the development of joint diseases has been scarcely studied. The objective of this review is to discuss the evidence regarding the mechanisms by which Cd exposure, through tobacco smoke, may lead to the development of osteoarthritis (OA), osteoporosis (OP), and rheumatoid arthritis (RA). There's evidence suggesting a string association between moderate to severe OA development and tobacco use, and that a higher blood concentration of Cd can trigger oxidative stress (OS) and inflammation, favoring cartilage loss. At the bone level, the Cd that is inhaled through tobacco smoke affects bone mineral density, resulting in OP mediated by a decrease in the antioxidant enzymes, which favors the bone resorption process. In RA, tobacco use promotes the citrullination process through Cd exposure and increases OS and inflammation. Understanding how tobacco use can increase the damage at the articular level mediated by a toxic metal, i.e., Cd, is important. Finally, we propose prevention, control, and treatment strategies for frequently disabling diseases, such as OA, OP, and RA to reduce its prevalence in the population.

Inflammatory Cytokine-Producing Cells and Inflammation Markers in the Synovium of Osteoarthritis Patients Evidenced in Human Herpesvirus 7 Infection.

A direct association between joint inflammation and the progression of osteoarthritis (OA) has been proposed, and synovitis is considered a powerful driver of the disease. Among infections implicated in the development of joint disease, human herpesvirus 7 (HHV-7) infection remains poorly characterized. Therefore, we assessed synovitis in OA patients; determined the occurrence and distribution of the HHV-7 antigen within the synovial membrane of OA-affected subjects; and correlated plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin-6 (IL-6), and TNF expressed locally within lesioned synovial tissues with HHV-7 observations, suggesting differences in persistent latent and active infection. Synovial HHV-7, CD4, CD68, and TNF antigens were detected immunohistochemically. The plasma levels of TNF and IL-6 were measured by an enzyme-linked immunosorbent assay. Our findings confirm the presence of persistent HHV-7 infection in 81.5% and reactivation in 20.5% of patients. In 35.2% of patients, virus-specific DNA was extracted from synovial membrane tissue samples. We evidenced the absence of histopathologically detectable synovitis and low-grade changes in the majority of OA patients enrolled in the study, in both HHV-7 PCR+ and HHV-7 PCR‒ groups. The number of synovial CD4-positive cells in the HHV-7 polymerase chain reaction (PCR)+ group was significantly higher than that in the HHV-7 PCR‒ group. CD4- and CD68-positive cells were differently distributed in both HHV-7 PCR+ and HHV-7 PCR‒ groups, as well as in latent and active HHV-7 infection. The number of TNF+ and HHV-7+ lymphocytes, as well as HHV-7+ vascular endothelial cells, was strongly correlated. Vascular endothelial cells, especially in the case of infection reactivation, appeared vulnerable. The balance between virus latency and reactivation is a long-term relationship between the host and infectious agent, and the immune system appears to be involved in displaying overreaction when a shift in the established equilibrium develops.

Daily interleukin-1β variability in women with rheumatoid arthritis associated with fibromyalgia

Annotation. Disorders of circadian rhythms are considered to be one of the factors associated with the development of joint diseases. In patients with rheumatoid arthritis (RA) disorders of the neurohumoral regulation of circadian rhythms is a factor in the increased production of inflammatory cytokines in the joint tissues. In 30 % of RA patients, concomitant fibromyalgia (FM) is found, in which disorders of circadian regulation can deepen. Circadian features of the production of pain mediators and inflammation in RA patients with comorbid fibromyalgia (FM) have not been established. The aim of this study was to investigate the daily variability of serum interleukin-1β levels in RA patients depending on the comorbidity of FM. Materials and methods: 49 patients with rheumatoid arthritis (RA) (100 % female) aged 46.8 (39–53) years, with moderate and high disease activity (DAS28>3.2), of which 21 (42.9 %) patients with concomitant fibromyalgia (FM). Diagnosis of RA was established by ACR/EULAR criteria (2010), FM was diagnosed by mACR 2010. Blood sampling was performed twice daily (at 08-00 and at 20-00), the level of IL-1β in the blood was determined by enzyme immunoassay. The studies were conducted according to bioethical standards. Statistical processing of the results was performed by SPSS Statistics 22.0. Results: In RA patients circadian fluctuations of IL-1β level in blood were registered. IL-1β levels (08-00) in the morning was higher (1.2–1.3 times) than in the evening (20-00). In the presence of comorbid FM, patients with RA had significant increase in evening and average daily levels of IL-1β (1.3–1.6 times) than in RA patients without FM. Daily fluctuations of IL-1β correlate with RA activity and the fibromyalgia scale. Conclusions: In RA patients disorders of the circadian production of proinflammatory IL-1β, which are exacerbated under FM conditions, were detected. Increasing evening production of IL-1β correlated with the prevalence of pain index in RA patients with FM. Thus, disorders of IL-1β circadian production in RA patients can be integrated into the mechanisms of central sensitization and FM development.

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes.

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

An update on the risks and benefits of neutering in dogs

Surgical neutering of pet dogs has generally been regarded as an important means of population control that also has both health-related and behavioural benefits. Perceived health-related benefits include prevention of mammary tumours and pyometra in bitches and testicular and prostatic disease in male dogs. Perceived behavioural benefits are associated with a reduction in sexually-dimorphic behaviours including roaming, mounting and urine marking in male dogs, and problem behaviours associated with seasons or phantom pregnancies in bitches. In recent years a number of research studies have suggested that the health-related benefits of neutering may be less marked than was once believed, and that neutering may also have negative health-related effects, particularly associated with the development of joint disease and neoplasia. While this is concerning, there are factors that may influence the validity of the results of these studies and the degree to which they can be reliably extended to all dogs. This also applies to the studies that have looked at the effect of neutering on behaviour in dogs. In the absence of clear information particularly regarding the health-related effects of neutering it is currently very difficult to give neutering guidelines that will be suitable for all dogs, and that will reliably reduce the risks of them developing specific diseases. This may change as more research becomes available. Until then, it is better to work out the risks and benefits of neutering for each individual dog based on the risk of unwanted mating occurring and the presence or absence of problem behaviours influenced by sex hormones, in addition to the owner's preference.

MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice.

The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b) in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold) from the onset of joint bleeding (1, 3, 7 and 24 h) until six bleeding episodes (up to 90 days). To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV) 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α) and hypoxia inducing factor 2α (HIF-2α), ~70% and ~34%, respectively) in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs) 1, 3, 9 and 14 (~14% to 60%) in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease.

Associations between hoof shape and the position of the frontal plane ground reaction force vector in walking horses

AIMS: To determine the frontal plane position of the ground reaction force vector at its centre of pressure under the hoof of walking horses, and its projection through the distal limb joints, and to relate this to hoof geometric measurements.METHODS: Reflective markers were glued to the forelimb hooves and skin of 26 horses, over palpable landmarks representing centres of the coffin, fetlock and carpal joints, and the dorsal toe at its most distal point. A 4-camera kinematic system recorded the position of these markers as the horse walked in hand across a force platform, to generate a frontal plane representation of the ground reaction force vector passing between the markers at the joints. The position of the vector was calculated as the relative distance between the lateral (0%) and medial (100%) markers at each joint. Digital photos were taken of the hoof in frontal and sagittal views to determine hoof geometric measurements. Associations between these and the position of the force vector at each joint were examined using Pearson correlation coefficients.RESULTS: Mean vector position for both forelimbs at the toe, coffin, fetlock and carpal joint was 50.1 (SD 8.9), 53.0 (SD 9.2), 54.6 (SD 11.4) and 50.5 (SD17.3)%, respectively, of the distance between the lateral and medial sides of the joint in the frontal plane. Across all four joints, the vector position was slightly more medial (2–4%) for the right than left limb (p>0.05). Medial hoof wall angle was correlated (p<0.05) with force vector position at the fetlock (r=−0.402) and carpal (r=−0.317) joints; lateral hoof wall angle with vector position at the toe (r=0.288) and carpal (r=−0.34) joint, and medial hoof wall height with vector position at the fetlock (r=−0.306) and carpal (r=−0.303) joints.CONCLUSION: The position of the two-dimensional frontal plane ground reaction force vector at the toe, and at the fetlock and carpal joints was associated with hoof shape. Mediolateral hoof balance has been shown in vitro to affect articular forces, which may be a factor in development of joint disease. The effect of hoof shape needs to be evaluated at faster gaits to determine the potential for joint injury in the presence of larger forces.

Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future.

Recurrent joint bleeding, leading to the development of joint disease and arthropathy, are the hallmarks of haemophilia. Prevention of bleeding through prophylaxis, rather than the on-demand treatment of bleeding events when they occur, is considered the gold standard of treatment for severe haemophilia. The original aim of prophylaxis was to avoid arthropathy by changing the bleeding phenotype from a severe to moderate form. While the use of prophylaxis has undoubtedly improved patients’ outcome and quality of life (QoL) by preventing bleeding and joint disease progression, challenges remain, and there is a growing awareness that prophylaxis may also benefit vulnerable patients with mild/moderate haemophilia. The ultimate treatment goal for haemophilia is the absence of joint bleeds, and ensuing joint disease and arthropathy, for all. Members of the Zurich Haemophilia Forum convened for their tenth meeting in November 2012 to discuss current and future treatments for haemophilia and the aims to mitigate disease severity and prevent arthropathy. In particular, discussions regarding the concept of an optimal trough level - what this should be and how to achieve it (now and in the future) for haemophilia patients without inhibitors - are summarised in this report.

Arthritis in Rats Caused by Pleuropneumonia-Like Micro-Organisms and the Relationship of Similar Organisms to Human Rheumatism

The etiology of rheumatoid arthritis has remained obscure in spite of considerable investigation. The difficulty of its elucidation is increased by the fact that no experimental animal has yet been found in which it is possible to reproduce the disease or in which a strictly comparable disease has occurred spontaneously. Until comparatively recent, all attempts to produce arthritis in animals by the injection of microorganisms, either directly into joints, into the blood stream or by the establishment of foci elsewhere, have led to the development of joint disease which bears only slight resemblance to the typical changes of rheumatoid arthritis. The animal arthritis produced by bacteria is an acute process, usually markedly purulent, which may go on to a chronic state in which the late stages of the inflammatory process suggest, to a certain extent, the pathological changes found in rheumatoid arthritis, but the animal disease lacks many of the outstanding features of the human, particularly the phenomenon of recurrences, and also destruction of cartilage under a granulation tissue pannus. Recently there have appeared reports of spontaneous arthritis occurring in rats and mice, which have given new impetus to attempts to find an animal disease which resembles more closely rheumatoid arthritis and also to investi-