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NPJ Microgravity Aug 2023The senses of limb position and movement become degraded in low gravity. One explanation is a gravity-dependent loss of fusimotor activity. In low gravity, position and... (Review)
Review
The senses of limb position and movement become degraded in low gravity. One explanation is a gravity-dependent loss of fusimotor activity. In low gravity, position and movement sense accuracy can be recovered if elastic bands are stretched across the joint. Recent studies using instrumented joysticks have confirmed that aiming and tracking accuracy can be recovered in weightlessness by changing viscous and elastic characteristics of the joystick. It has been proposed that the muscle spindle signal, responsible for generating position sense in the mid-range of joint movement, is combined with input from joint receptors near the limits of joint movement to generate a position signal that covers the full working range of the joint. Here it is hypothesised that in low gravity joint receptors become unresponsive because of the loss of forces acting on the joint capsule. This leads to a loss of position and movement sense which can be recovered by imposing elastic forces across the joint.
PubMed: 37567869
DOI: 10.1038/s41526-023-00318-8 -
Journal of Physical Therapy Science Dec 2023[Purpose] We investigated morphological and histopathological changes in the joint capsule of rats with aging. [Materials and Methods] A total of 18 male Wistar rats...
[Purpose] We investigated morphological and histopathological changes in the joint capsule of rats with aging. [Materials and Methods] A total of 18 male Wistar rats were categorized into two groups: the control group (n=8), and the aged group (n=10). The aged group was reared until 75 weeks of age, while the control group was maintained until 11 weeks of age. At the end of the experiment period, the knee joints were sampled, joint capsules were subjected to histopathological analysis, and their thickness was measured. [Results] The joint capsule in the aging group exhibited significantly greater thickness compared to the control group. Histopathological examination revealed distinct differences between the two groups. The control group displayed gaps between the collagen fibers in the posterior joint capsule, along with loosely overlapping connective tissue and the presence of fat cells. Conversely, in the aged group's joint capsule, these gaps between the collagen fibers almost disappeared and fibers became densely packed and thickened. [Conclusion] These results were similar to our previous study in rats with immobilized hindlimb knee joints. Similar findings, including collagen fiber thickening, densification in the joint capsule, and reduced hindlimb knee joint range of motion, were consistent with those observed in the present investigation.
PubMed: 38075508
DOI: 10.1589/jpts.35.763 -
Stem Cell Research & Therapy Sep 2023Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease of unknown etiology. The most common form of this disease is chronic inflammatory arthritis, which... (Review)
Review
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease of unknown etiology. The most common form of this disease is chronic inflammatory arthritis, which begins with inflammation of the synovial membrane of the affected joints and eventually leads to disability of the affected limb. Despite significant advances in RA pharmaceutical therapies and the availability of a variety of medicines on the market, none of the available medicinal therapies has been able to completely cure the disease. In addition, a significant percentage (30-40%) of patients do not respond appropriately to any of the available medicines. Recently, mesenchymal stromal cells (MSCs) have shown promising results in controlling inflammatory and autoimmune diseases, including RA. Experimental studies and clinical trials have demonstrated the high power of MSCs in modulating the immune system. In this article, we first examine the mechanism of RA disease, the role of cytokines and existing medicinal therapies. We then discuss the immunomodulatory function of MSCs from different perspectives. Our understanding of how MSCs work in suppressing the immune system will lead to better utilization of these cells as a promising tool in the treatment of autoimmune diseases.
Topics: Humans; Arthritis, Rheumatoid; Synovial Membrane; Mesenchymal Stem Cells; Cytokines; Inflammation
PubMed: 37741991
DOI: 10.1186/s13287-023-03473-7 -
Seminars in Arthritis and Rheumatism Feb 2024Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis (RA), 40% of patients show poor clinical response, and there... (Review)
Review
BACKGROUND
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis (RA), 40% of patients show poor clinical response, and there is an imperative to unravel the molecular pathways and mechanisms underlying non-response and disease progression. 5-20% of RA individuals do not respond to all current medications including biologic and targeted therapies, which suggests that distinct pathogenic processes underlie multi-drug refractoriness.
OBJECTIVES
In this brief review we discuss advances from recent studies in precision medicine in rheumatoid arthritis.
METHODS
Bulk RNA-Sequencing of synovial biopsies from RA individuals combined with histology and deep clinical phenotyping has revealed substantial insights into divergent pathogenic pathways which lead to disease progression and illuminated mechanisms underlying failure to response to specific treatments. Biopsy-driven randomised controlled trials, such as R4RA and the forthcoming STRAP trial, have enabled the development of machine learning predictive models for predicting response to different therapies.
RESULTS
In the Pathobiology of Early Arthritis Cohort (PEAC), gene expression analysis showed that individuals could be classified into three gene expression subgroups which correlated with histopathotypes defined by histological markers: pauci-immune fibroid pathotype characterised by fibroblasts and an absence of immune inflammatory cells; diffuse-myeloid pathotype characterised by macrophage influx; and the lympho-myeloid pathotype delineated by the presence of B cells, but typically containing a complex inflammatory infiltrate with ectopic lymphoid structure formation. In the R4RA biopsy-driven randomised controlled trial, patients were randomised to either rituximab or tocilizumab. Comprehensive analysis of synovial biopsies pre/post-treatment identified gene signatures of response associated with pathogenic pathways which could be tracked over time. A group of true refractory patients were identified who had failed anti-TNF prior to the study (it was an entry criterion) and then subsequently failed both trial biologics during the trial. RNA-Seq analysis and digital spatial profiling identified specific cell types including DKK3 fibroblasts as being associated with the refractory state. We identified machine learning predictive models based on specific gene signatures which were able to predict future response to therapy as well as the refractory state.
CONCLUSIONS
RNA-sequencing of synovial biopsies has enabled substantial progress in understanding disease endotypes in RA and identifying synovial gene signatures which predict prognosis and future response to treatment.
Topics: Humans; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Arthritis, Rheumatoid; Disease Progression; RNA; Synovial Membrane; Randomized Controlled Trials as Topic
PubMed: 38008706
DOI: 10.1016/j.semarthrit.2023.152329 -
International Immunopharmacology May 2024Resident synoviocytes and synovial microvasculature, together with immune cells from circulation, contribute to pannus formation, the main pathological feature of... (Review)
Review
Resident synoviocytes and synovial microvasculature, together with immune cells from circulation, contribute to pannus formation, the main pathological feature of rheumatoid arthritis (RA), leading to destruction of adjacent cartilage and bone. Seeds, fibroblast-like synoviocytes (FLSs), macrophages, dendritic cells (DCs), B cells, T cells and endothelial cells (ECs) seeds with high metabolic demands undergo metabolic reprogramming from oxidative phosphorylation to glycolysis in response to poor soil of RA synovium with hypoxia, nutrient deficiency and inflammatory stimuli. Glycolysis provides rapid energy supply and biosynthetic precursors to support pathogenic growth of these seeds. The metabolite lactate accumulated during this process in turn condition the soil microenvironment and affect seeds growth by modulating signalling pathways and directing lactylation modifications. This review explores in depth the survival mechanism of seeds with high metabolic demands in the poor soil of RA synovium, providing useful support for elucidating the etiology of RA. In addition, we discuss the role and major post-translational modifications of proteins and enzymes linked to glycolysis to inspire the discovery of novel anti-rheumatic targets.
Topics: Arthritis, Rheumatoid; Humans; Glycolysis; Animals; Synovial Membrane; Synoviocytes; Signal Transduction
PubMed: 38603855
DOI: 10.1016/j.intimp.2024.111913 -
Anatomia, Histologia, Embryologia Sep 2023The knee joint capsules composed of a fibrous layer and a synovial layer. The knee meniscus consists of the superficial network, lamellar layer, tie fibre and...
The knee joint capsules composed of a fibrous layer and a synovial layer. The knee meniscus consists of the superficial network, lamellar layer, tie fibre and circumferential bundles. However, the continuous structure of the knee joint capsule and meniscus has not been reported. Fetal and adult pigs were used to investigate the structural relationship between the stifle joint capsule and meniscus based on the gross anatomy and histological findings. In the gross anatomical examination, the joint capsule appeared to have separated attachments to the meniscus, except for the lower aspect of the popliteal hiatus. Histologically, the lower half of the popliteal hiatus was found to have separated attachments, with vessels running between the attachments of the joint capsules. The synovial layer of the joint capsule continued to the superficial network, and the fibrous layer of the joint capsule continued to the lamellar layer and tie fibres. There were two routes of arterial entry into the meniscus: intracapsular and intercapsular. It appeared that the presence of separated attachments of the joint capsule was necessary to allow the intercapsular route. This study clarified for the first time the routes of feeding vessels entering the meniscus and proposed to call this entry point the meniscus hilum. We consider that this detailed anatomical information is important for understanding the continuation between the joint capsule and the meniscus.
Topics: Animals; Swine; Knee Joint; Meniscus; Synovial Membrane; Fetus; Menisci, Tibial
PubMed: 37306076
DOI: 10.1111/ahe.12938 -
International Immunopharmacology Aug 2023Extracellular matrix (ECM) is a three-dimensional network entity composed of extracellular macromolecules. ECM in synovium not only supports the structural integrity of... (Review)
Review
Extracellular matrix (ECM) is a three-dimensional network entity composed of extracellular macromolecules. ECM in synovium not only supports the structural integrity of synovium, but also plays a crucial role in regulating homeostasis and damage repair response in synovium. Obvious disorders in the composition, behavior and function of synovial ECM will lead to the occurrence and development of arthritis diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis (PsA). Based on the importance of synovial ECM, targeted regulation of the composition and structure of ECM is considered to be an effective measure for the treatment of arthritis disease. This paper reviews the current research status of synovial ECM biology, discusses the role and mechanism of synovial ECM in physiological status and arthritis disease, and summarizes the current strategies for targeting synovial ECM to provide information for the pathogenesis, diagnosis and treatment of arthritis disease.
Topics: Humans; Arthritis, Psoriatic; Synovial Membrane; Arthritis, Rheumatoid; Gout; Extracellular Matrix; Homeostasis
PubMed: 37331300
DOI: 10.1016/j.intimp.2023.110453 -
Biochemical Pharmacology Sep 2023Rheumatoid arthritis (RA) is a common autoimmune disease marked by immune cell activation and chronic inflammation in the synovium accompanied by osteoclast activation...
Rheumatoid arthritis (RA) is a common autoimmune disease marked by immune cell activation and chronic inflammation in the synovium accompanied by osteoclast activation and local joint destruction. Increased levels of the adipokine nesfatin-1 in RA synovium are associated with proinflammatory cytokines. Our analysis of datasets from the Gene Expression Omnibus (GEO) database and synovial tissue samples from RA patients revealed that these had higher levels of nesfatin-1 and osteoclast markers compared with normal synovium. These findings were the same in tissue samples from mice with collagen-induced arthritis (CIA) and normal healthy controls. RNA sequencing analysis revealed that nesfatin-1 increased levels of bone morphogenetic protein-5 (BMP5) expression via JAK/STAT signaling in RA synovial fibroblasts. Finally, we found that nesfatin-1 short hairpin RNA reduced BMP5 and osteoclast formation in CIA mice. These findings provide new insights into the pathogenesis of RA.
Topics: Animals; Mice; Arthritis, Experimental; Arthritis, Rheumatoid; Fibroblasts; Osteoclasts; Osteogenesis; Synovial Membrane
PubMed: 37481139
DOI: 10.1016/j.bcp.2023.115687 -
International Journal of Immunogenetics Jun 2024Osteoarthritis (OA) is one of the most common degenerative diseases characterised by joint pain, swelling and decreased mobility, with its main pathological features... (Review)
Review
Osteoarthritis (OA) is one of the most common degenerative diseases characterised by joint pain, swelling and decreased mobility, with its main pathological features being articular synovitis, cartilage degeneration and osteophyte formation. Inflammatory cytokines and chemokines secreted by activated immunocytes can trigger various inflammatory and immune responses in articular cartilage and synovium, contributing to the genesis and development of OA. A series of monocyte/macrophage chemokines, including monocyte chemotaxis protein (MCP)-1/CCL2, MCP2/CCL8, macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, MIP-3α/CCL20, regulated upon activation, normal T-cell expressed and secreted /CCL5, CCL17 and macrophage-derived chemokine/CCL22, was proven to transmit cell signals by binding to G protein-coupled receptors on recipient cell surface, mediating and promoting inflammation in OA joints. However, the underlying mechanism of these chemokines in the pathogenesis of OA remains still elusive. Here, published literature was reviewed, and the function and mechanisms of monocyte/macrophage chemokines in OA pathogenesis were summarised. The symptoms and disease progression of OA were found to be effectively alleviated when the expression of these chemokines is inhibited. Elucidating these mechanisms could contribute to further understand how OA develops and provide potential targets for the early diagnosis of arthritis and drug treatment to delay or even halt OA progression.
Topics: Humans; Osteoarthritis; Chemokines; Monocytes; Macrophages; Animals; Cartilage, Articular; Synovial Membrane
PubMed: 38462560
DOI: 10.1111/iji.12664 -
Journal of Autoimmunity Jul 2023The aim of this study was to assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA). Synovial LAT1 expression...
The aim of this study was to assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA). Synovial LAT1 expression in RA was monitored by immunohistochemistry and transcriptomic datasets. The contribution of LAT1 to gene expression and immune synapse formation was assessed by RNA-sequencing and total internal reflection fluorescent (TIRF) microscopy, respectively. Mouse models of RA were used to assess the impact of therapeutic targeting of LAT1. LAT1 was strongly expressed by CD4 T cells in the synovial membrane of people with active RA and the level of expression correlated with levels of ESR and CRP as well as DAS-28 scores. Deletion of LAT1 in murine CD4 T cells inhibited the development of experimental arthritis and prevented the differentiation of CD4 T cells expressing IFN-γ and TNF-α, without affecting regulatory T cells. LAT1 deficient CD4 T cells demonstrated reduced transcription of genes associated with TCR/CD28 signalling, including Akt1, Akt2, Nfatc2, Nfkb1 and Nfkb2. Functional studies using TIRF microscopy revealed a significant impairment of immune synapse formation with reduced recruitment of CD3ζ and phospho-tyrosine signalling molecules in LAT1 deficient CD4 T cells from the inflamed joints but not the draining lymph nodes of arthritic mice. Finally, it was shown that a small molecule LAT1 inhibitor, currently undergoing clinical trials in man, was highly effective in treating experimental arthritis in mice. It was concluded that LAT1 plays a critical role in activation of pathogenic T cell subsets under inflammatory conditions and represents a promising new therapeutic target for RA.
Topics: Mice; Animals; Synovial Membrane; Arthritis, Rheumatoid; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Signal Transduction; Arthritis, Experimental; CD4-Positive T-Lymphocytes
PubMed: 37229811
DOI: 10.1016/j.jaut.2023.103031