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Bioscience Trends Nov 2020The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work... (Review)
Review
The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.
Topics: Arthritis, Rheumatoid; Biological Factors; Bone Density Conservation Agents; Cadherins; Humans; Joint Capsule; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Proteins; RANK Ligand; Recombinant Proteins; Signal Transduction; Synovial Fluid
PubMed: 32908076
DOI: 10.5582/bst.2020.03253 -
Arthritis Research & Therapy Apr 2021Osteoarthritis (OA) has long been regarded as a disease of cartilage degeneration, whereas mounting evidence implies that low-grade inflammation contributes to OA. Among... (Review)
Review
OBJECTIVE
Osteoarthritis (OA) has long been regarded as a disease of cartilage degeneration, whereas mounting evidence implies that low-grade inflammation contributes to OA. Among inflammatory cells involved, macrophages play a crucial role and are mediated by the local microenvironment to exhibit different phenotypes and polarization states. Therefore, we conducted a systematic review to uncover the phenotypic alterations of macrophages during OA and summarized the potential therapeutic interventions via modulating macrophages.
METHODS
A systematic review of multiple databases (PubMed, Web of Science, ScienceDirect, Medline) was performed up to February 29, 2020. Included articles were discussed and evaluated by two independent reviewers. Relevant information was analyzed with a standardized and well-designed template.
RESULTS
A total of 28 studies were included. Results were subcategorized into two sections depending on sources from human tissue/cell-based studies (12 studies) and animal experiments (16 studies). The overall observation indicated that M1 macrophages elevated in both synovium and circulation during OA development, along with lower numbers of M2 macrophages. The detailed alterations of macrophages in both synovium and circulation were listed and analyzed. Furthermore, interventions against OA via regulating macrophages in animal models were highlighted.
CONCLUSION
This study emphasized the importance of the phenotypic alterations of macrophages in OA development. The classical phenotypic subcategory of M1 and M2 macrophages was questionable due to controversial and conflicting results. Therefore, further efforts are needed to categorize macrophages in an exhaustive manner and to use advanced technologies to identify the individual roles of each subtype of macrophages in OA.
Topics: Animals; Humans; Inflammation; Macrophages; Osteoarthritis; Phenotype; Synovial Membrane
PubMed: 33838669
DOI: 10.1186/s13075-021-02457-3 -
Autoimmunity Reviews Mar 2021Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical... (Review)
Review
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical importance in the initiation and perpetuation of synovitis in RA, they can function as antigen presenting cells leading to T-cell dependent B-cell activation, assume a variety of inflammatory cell states with the production of destructive cytokines, but also contribute to tissue homeostasis/repair. The recent development of high-throughput technologies, including bulk and single cells RNA-sequencing, has broadened our understanding of synovial cell diversity, and opened novel perspectives to the discovery of new potential therapeutic targets in RA. In this review, we will focus on the relationship between the synovial macrophage infiltration and clinical disease severity and response to treatment. We will then provide a state-of-the-art picture of the biological roles of synovial macrophages and distinct macrophage subsets described in RA. Finally, we will review the effects of approved conventional and biologic drugs on the synovial macrophage component and highlight the therapeutic potential of future strategies to re-program macrophage phenotypes in RA.
Topics: Arthritis, Rheumatoid; Humans; Macrophages; Synovial Membrane; Synovitis; T-Lymphocytes
PubMed: 33476818
DOI: 10.1016/j.autrev.2021.102758 -
Frontiers in Immunology 2024Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the... (Review)
Review
Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1 phenotype is restricted to the synovial lining layer. In contrast, the THY1 phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells.
Topics: Humans; Osteoarthritis; Fibroblasts; Animals; Phenotype; Fibrosis; Synoviocytes; Synovial Membrane
PubMed: 38895122
DOI: 10.3389/fimmu.2024.1385006 -
Current Opinion in Rheumatology Jan 2024Synovial fibroblasts are the central cells of connective tissue homeostasis. In rheumatoid arthritis (RA) tissue, synovial fibroblasts are activated because of the... (Review)
Review
PURPOSE OF REVIEW
Synovial fibroblasts are the central cells of connective tissue homeostasis. In rheumatoid arthritis (RA) tissue, synovial fibroblasts are activated because of the proinflammatory environment very early in the disease. Epigenetic alterations in RASF result in a permanently activated stage, and activated RASF are involved in many processes of RA pathophysiology. Therefore, several recent findings of the last 18 months with focus on RASF activation and function are summarized.
RECENT FINDINGS
RASF activation because of a profoundly altered epigenome leads to an invasive phenotype with increased migration, adhesion and invasion into cartilage, which was further characterized in several studies. RASF subtypes and subtype dynamics were evaluated using high-resolution techniques to better understand RASF pathophysiology. Many studies addressing interactions with immune or stromal cell types have been published showing that RASF interact with many different cell types contributing not only to their own activation and pro-inflammatory response but also to the activation of the other cells.
SUMMARY
Highly interesting findings revealing mechanisms of RASF activation and altered functions have been published, RASF subsets further characterized, and interactions with cell types elucidated, which all contribute to a better understanding of the role of RASF in RA development and progression.
Topics: Humans; Synovial Membrane; Arthritis, Rheumatoid; Fibroblasts
PubMed: 37720975
DOI: 10.1097/BOR.0000000000000978 -
International Journal of Environmental... Jul 2021Osteoarthritis (OA) of the glenohumeral (GH) joint is a common cause of shoulder pain, resulting in considerable invalidity. Unfortunately, the study of its pathogenesis...
Arthroscopic Tenotomy of the Long Head of the Biceps Tendon and Section of the Anterior Joint Capsule Produce Moderate Osteoarthritic Changes in an Experimental Sheep Model.
Osteoarthritis (OA) of the glenohumeral (GH) joint is a common cause of shoulder pain, resulting in considerable invalidity. Unfortunately, the study of its pathogenesis is challenging. Models of OA are necessary to identify specific targets for therapy and to be able to interfere with the development and evolution of OA. This study aims to assess the effect of an arthroscopic tenotomy of the long head of the biceps tendon (LHBT) and section of the anterior glenohumeral joint capsule on the ovine glenohumeral joint. In addition, the authors aim to validate and evaluate the reliability of a modified semi-quantitative MRI score to assess joint degeneration in a sheep's shoulder. Eight skeletally mature sheep received an arthroscopic tenotomy of the LHBT and section of the anterior joint capsule and were euthanized four months after surgery. All animals tolerated the surgery well, and no complication was recorded for six weeks. Moderate degenerative changes to the ovine shoulder joint were found on MRI and histological evaluation. The arthroscopic tenotomy of the LHBT and the anterior glenohumeral joint capsule section caused moderate degenerative changes to the ovine shoulder joint.
Topics: Animals; Joint Capsule; Reproducibility of Results; Rotator Cuff Injuries; Sheep; Shoulder Joint; Tendons; Tenotomy
PubMed: 34299937
DOI: 10.3390/ijerph18147471 -
Knee Surgery, Sports Traumatology,... Jul 2021To analyze biopsy samples from the subscapularis tendon and from the joint capsule from male patients with subacromial impingement syndrome and compare them with samples...
PURPOSE
To analyze biopsy samples from the subscapularis tendon and from the joint capsule from male patients with subacromial impingement syndrome and compare them with samples from male patients with post-traumatic recurrent shoulder instability, to detect increased inflammatory activity that might be present inside the humeroscapular joint.
METHODS
Twenty male patients scheduled for surgery for either subacromial decompression or Bankart reconstruction were included. Four biopsies from each patient were obtained during surgery from the capsule and the subscapularis tendon. Each specimen was analyzed for TNF-α, IL-6, CD-3 and CD-72. Multiplex fluorescence immunohistochemistry was performed on histological samples from the capsule and tendon to demonstrate the level of inflammatory markers. Fluorescence microscope images were acquired using an automated scanning system. On each slide, the number of pixels was registered and used in the analyses.
RESULTS
The subacromial impingement syndrome group comprised eight patients, median age 53 (45-74) years, while the instability group 12, median age 27 (22-48) years (p < 0.00001). The amount of IL-6 and TNF-α was significantly higher in the subscapularis tendon of the patients with subacromial impingement syndrome compared with instability patients (p = 0.0015 and p = 0.0008 respectively). In the capsular samples, significantly higher amount of TNF-α and CD-72 was found in patients with subacromial impingement syndrome compared with instability patients (p < 0.0001 for both). On the other hand, the amount of CD-3 was significantly higher in the instability group (p = 0.0013).
CONCLUSIONS
This study provides evidence that an extended inflammatory process is present, not only in the subacromial bursa but also in the glenohumeral joint in patients with subacromial impingement syndrome.
LEVEL OF EVIDENCE
Level III.
CLINICAL RELEVANCE
To develop a treatment targeted towards intra-articular inflammatory cytokines appears appealing.
Topics: Aged; Biomarkers; Biopsy; Bursa, Synovial; Cytokines; Decompression, Surgical; Humans; Inflammation; Interleukin-6; Joint Capsule; Joint Instability; Male; Middle Aged; Plastic Surgery Procedures; Rotator Cuff; Shoulder; Shoulder Impingement Syndrome; Shoulder Joint; Tendons; Tumor Necrosis Factor-alpha
PubMed: 32356046
DOI: 10.1007/s00167-020-05992-9 -
Journal of Biomechanical Engineering May 2022The facet capsule ligament (FCL) is a structure in the lumbar spine that constrains motions of the vertebrae. Subfailure loads can produce microdamage resulting in...
The facet capsule ligament (FCL) is a structure in the lumbar spine that constrains motions of the vertebrae. Subfailure loads can produce microdamage resulting in increased laxity, decreased stiffness, and altered viscoelastic responses. Therefore, the purpose of this investigation was to determine the mechanical and viscoelastic properties of the FCL under various magnitudes of strain from control samples and samples that had been through an impact protocol. Two hundred FCL tissue samples were tested (20 control and 180 impacted). Impacted FCL tissue samples were obtained from functional spinal units that had been exposed to one of nine subfailure impact conditions. All specimens underwent the following loading protocol: preconditioning with five cycles of 5% strain, followed by a 30 s rest period, five cycles of 10% strain, and 1 cycle of 10% strain with a hold duration at 10% strain for 240 s (4 min). The same protocol was followed for 30% and 50% strain. Measures of stiffness, hysteresis, and force-relaxation were computed. No significant differences in stiffness were observed for impacted specimens in comparison to control. Impacted specimens from the 8 g flexed and 11 g flexed and neutral conditions exhibited greater hysteresis during the cyclic-30% and cyclic-50% portion of the protocol in comparison to controls. In addition, specimens from the 8 g and 11 g flexed conditions resulted in greater stress decay for the 50%-hold conditions. Results from this study demonstrate viscoelastic changes in FCL samples exposed to moderate and highspeed single impacts in a flexed posture.
Topics: Animals; Biomechanical Phenomena; Joint Capsule; Ligaments, Articular; Lumbar Vertebrae; Stress, Mechanical; Swine; Zygapophyseal Joint
PubMed: 35244145
DOI: 10.1115/1.4054022 -
Antimicrobial Agents and Chemotherapy Mar 2021The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in...
The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty and to establish the pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125 individuals using a nonlinear mixed-effects model. The pharmacodynamic index target value obtained from our results indicates the probability of maintaining CFZ trough and hip joint capsule concentrations exceeding the MIC of 1 mg/liter to account for methicillin-susceptible (MSSA). We estimated the population pharmacokinetics using a two-compartment model. The estimated population pharmacokinetic parameters were as follows: clearance (CL) (liters/h) = 1.46 × (creatinine clearance [CL] [ml/min]/77), volume of distribution of the central compartment (V) (liters) = 7.5, central-hip joint capsule compartment clearance (Q) (liters/h) = 3.38, and volume of distribution in the hip joint capsule compartment (V) (liters) = 36.1. The probability of achieving concentrations exceeding the MIC for MSSA was approximately 100% for serum and 100% for the hip joint capsule at 3 h after the initial dose. Our findings suggest that population-based parameters are useful for evaluating CFZ pharmacokinetics and that individual dosages should be determined based on the dosage regimen that achieves and maintains adequate tissue CFZ concentration.
Topics: Anti-Bacterial Agents; Arthroplasty, Replacement, Hip; Cefazolin; Humans; Joint Capsule; Microbial Sensitivity Tests; Staphylococcus aureus
PubMed: 33526489
DOI: 10.1128/AAC.02114-20 -
Arthritis & Rheumatology (Hoboken, N.J.) May 2023Osteoarthritis (OA) exposes all joint tissues to physiologic stresses, increasing the need to clear apoptotic cells from tissues, including the synovium. We undertook...
OBJECTIVE
Osteoarthritis (OA) exposes all joint tissues to physiologic stresses, increasing the need to clear apoptotic cells from tissues, including the synovium. We undertook this study to assess the burden of apoptotic cells in synovial tissue in patients with late-stage knee OA and to investigate whether OA impairs the macrophage-mediated clearance of apoptotic cells via efferocytosis.
METHODS
Synovial tissue was collected from individuals with healthy knees and patients with late-stage knee OA during arthroplasty. Synovial apoptotic cell burden was assessed by immunofluorescence for cleaved caspase 3. Efferocytosis of apoptotic Jurkat cells by CD14+ synovial tissue macrophages and peripheral blood-derived macrophages was quantified using immunofluorescence microscopy. Effects of OA on macrophage-mediated efferocytosis were modeled by stimulating blood-derived macrophages with synovial fluid collected from individuals with healthy knees and patients with early- or late-stage knee OA.
RESULTS
Patients with late-stage knee OA had more apoptotic synovial cells compared to healthy individuals. There was a marked reduction in the fraction of synovial tissue macrophages engaging in efferocytosis and the quantity of material efferocytosed by individual macrophages in OA patients. Blood-derived macrophages exposed to synovial fluid from patients with knee OA recapitulated the defective efferocytosis, with the greatest effect from patients with early-stage knee OA and higher disease activity (pain and inflammation).
CONCLUSION
Apoptotic cells accumulate in the synovium of patients with late-stage knee OA. Our results suggest that OA impairs critical homeostatic functions of synovial macrophages, leading to accumulation of apoptotic cells.
Topics: Humans; Osteoarthritis, Knee; Inflammation; Synovial Membrane; Synovial Fluid; Macrophages
PubMed: 36448607
DOI: 10.1002/art.42412