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Orthopaedic Surgery Mar 2024Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle-aged and elderly people, characterized by joint pain and dysfunction. Macrophages are... (Review)
Review
Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle-aged and elderly people, characterized by joint pain and dysfunction. Macrophages are key players in OA pathology, and their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli in their microenvironment by changing their phenotypes to pro-inflammatory or anti-inflammatory phenotypes, which is called macrophage polarization. Macrophages accumulate and become polarized (M1 or M2) in many tissues, such as synovium, adipose tissue, bone marrow, and bone mesenchymal tissues in joints, while resident macrophages as well as other stromal cells, including fibroblasts, chondrocytes, and osteoblasts, form the joint and function as an integrated unit. In this study, we focus exclusively on synovial macrophages, adipose tissue macrophages, and osteoclasts, to investigate their roles in the development of OA. We review recent key findings related to macrophage polarization and OA, including pathogenesis, molecular pathways, and therapeutics. We summarize several signaling pathways in macrophage reprogramming related to OA, including NF-κB, MAPK, TGF-β, JAK/STAT, PI3K/Akt/mTOR, and NLRP3. Of note, despite the increasing availability of treatments for osteoarthritis, like intra-articular injections, surgery, and cellular therapy, the demand for more effective clinical therapies has remained steady. Therefore, we also describe the current prospective therapeutic methods that deem macrophage polarization to be a therapeutic target, including physical stimulus, chemical compounds, and biological molecules, to enhance cartilage repair and alleviate the progression of OA.
Topics: Aged; Middle Aged; Humans; Phosphatidylinositol 3-Kinases; Osteoarthritis; Macrophages; Synovial Membrane; Osteoclasts
PubMed: 38296798
DOI: 10.1111/os.13993 -
Arthritis Research & Therapy Dec 2023Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While...
OBJECTIVE
Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While macrophages play a pivotal role in the inflammatory process of OA, the mechanisms underlying their activation and polarization remain incompletely elucidated. This study aims to investigate the role of NOD2 as a reciprocal modulator of HMGB1/TLR4 signaling in macrophage activation and polarization during OA pathogenesis.
DESIGN
We examined NOD2 expression in the synovium and determined the impact of NOD2 on macrophage activation and polarization by knockdown and overexpression models in vitro. Paracrine effect of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes was evaluated under conditions of NOD2 overexpression. Additionally, the in vivo effect of NOD2 was assessed using collagenase VII induced OA model in mice.
RESULTS
Expression of NOD2 was elevated in osteoarthritic synovium. In vitro experiments demonstrated that NOD2 serves as a negative regulator of HMGB1/TLR4 signaling pathway. Furthermore, NOD2 overexpression hampered the inflammatory paracrine effect of macrophages on FLS and chondrocytes. In vivo experiments revealed that NOD2 overexpression mitigated OA in mice.
CONCLUSIONS
Supported by convincing evidence on the inhibitory role of NOD2 in modulating the activation and M1 polarization of synovial macrophages, this study provided novel insights into the involvement of innate immunity in OA pathogenesis and highlighted NOD2 as a potential target for the prevention and treatment of OA.
Topics: Animals; Mice; HMGB1 Protein; Macrophages; Osteoarthritis; Synovial Membrane; Toll-Like Receptor 4
PubMed: 38124066
DOI: 10.1186/s13075-023-03230-4 -
Molecular Immunology Jan 2024The primary pathological changes of rheumatoid arthritis (RA) include chronic synovial inflammation, bone destruction, and aggressive pannus formation on cartilage, in...
OBJECTIVE
The primary pathological changes of rheumatoid arthritis (RA) include chronic synovial inflammation, bone destruction, and aggressive pannus formation on cartilage, in which angiogenesis plays a critical role. B7-H3, an important immune checkpoint molecule, represents a novel target in tumor therapy and plays a significant role in the pathogenesis of autoimmune diseases. However, its biological mechanism in RA remains unclear.
METHODS
Hematoxylin-eosin (HE) staining and immunohistochemistry were used to explore the histological characteristics and expression of B7-H3, CD34, and vascular endothelial growth factor (VEGF) in patients with RA and collagen-induced arthritis (CIA) mice. ELISA was used to detect VEGF, soluble B7-H3, and disease markers in the peripheral blood of patients. A monoclonal anti-B7-H3 antibody was used to treat CIA mice by blocking B7-H3-mediated signaling.
RESULTS
The ELISA and HE staining results showed a positive correlation between the expression of B7-H3 and the degree of joint cavity destruction and pannus formation. B7-H3 expression also correlated with increased expression of the vessel biomarkers CD34 and VEGF. Anti-B7-H3 effectively reduced pannus formation in CIA mice.
CONCLUSION
B7-H3 modulates angiogenic activity in the joint synovium, demonstrating its therapeutic value in the context of RA.
Topics: Animals; Humans; Mice; Angiogenesis; Antibodies, Monoclonal; Arthritis, Experimental; Arthritis, Rheumatoid; Inflammation; Neovascularization, Pathologic; Synovial Membrane; Transcription Factors; Vascular Endothelial Growth Factor A
PubMed: 38134517
DOI: 10.1016/j.molimm.2023.12.002 -
Cureus Apr 2024Hallux valgus (HV) is a relatively frequent disease caused by a complicated structural malformation of the primary ray. The bunion or middle projection generated by the... (Review)
Review
Hallux valgus (HV) is a relatively frequent disease caused by a complicated structural malformation of the primary ray. The bunion or middle projection generated by the hallux's lateral displacement and pronation is merely one element of the three-dimensional abnormality. HV may trigger severe discomfort and affect joint kinematics. The specific kinematic cause is still unknown. Female age, gender, restrictive footwear, and heritage are risk indicators. HV frequently coexists along metatarsal adducts, equines contracture, hammertoe imperfection, and pes planus. HV is a frequent foot ailment with multiple, complicated, unknown etiology and course. HV has a preference for females. It is an ongoing condition for which there is no known treatment to reduce or prevent improvement. Fibrodysplasia ossificans progressiva (FOP) is distinguished by hereditary symmetrical HV deformities or symptoms that begin heterotopic calcification that is either idiopathic or caused by trauma, such as subcutaneous immunizations. Localized heterotopic calcification may be preceded by aggravating, recurring soft-tissue enlargements (flare-ups). Heterotopic calcification may happen anywhere; however, it most commonly impacts locations near the axial bone structure during the early/mild phases until advancing to the appendicular skeleton. As an effect of calcification affecting the flexibility of the joints, it might cause limitations in motion. The initial line of therapy focuses on non-surgical methods including night splinting, orthotics, and larger shoes. The next suggested line of action is surgical intervention if conservative therapy fails. Patients have good postoperative tolerance, and bone union often happens six to seven weeks after surgery. Stretching exercises help to restore function by extending shortened soft tissue and restoring range of motion (ROM). The goal of joint mobilization, a form of manual treatment method, is to extend the ligament, the soft tissue surrounding the limited joint, and the restricting joint capsule by applying modest amplitude passive movement to the joint components.
PubMed: 38779237
DOI: 10.7759/cureus.58750 -
Frontiers in Veterinary Science 2024Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and... (Review)
Review
Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and apoptosis and depletion of chondrocytes. OA progression is characterized by hyaline cartilage loss, chondrophyte and osteophyte formation, thickening of the joint capsule and function loss in the later stages. As the regenerative potential of cartilage is very limited and osteoarthritic changes are irreversible, prevention of OA, modulation of existing osteoarthritic joint inflammation, reducing joint pain and supporting joint function are the only options. Progression of OA and pain may necessitate surgical intervention with joint replacement or arthrodesis as end-stage procedures. In human medicine, the role of adipokines in the development and progression of OA has received increasing interest. At present, the known adipokines include leptin, adiponectin, visfatin, resistin, progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin. Adipokines have been demonstrated to play a pivotal role in joint homeostasis by modulating anabolic and catabolic balance, autophagy, apoptosis and inflammatory responses. In small animals, in terms of dogs and cats, naturally occurring OA has been clearly demonstrated as a clinical problem. Similar to humans, the etiology of OA is multifactorial and has not been fully elucidated. Humans, dogs and cats share many joint related degenerative diseases leading to OA. In this review, joint homeostasis, OA, adipokines and the most common joint diseases in small animals leading to naturally occurring OA and their relation with adipokines are discussed. The purpose of this review is highlighting the translational potential of OA and adipokines research in small animal patients.
PubMed: 38831954
DOI: 10.3389/fvets.2024.1193702 -
Annals of the Rheumatic Diseases Sep 2023Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to...
OBJECTIVES
Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of rheumatoid arthritis (RA).
METHODS
Primary macrophages and fibroblast-like synoviocytes were cultured with aaRSs. aaRS-induced cytokine production including IL-6 and TNF-α was detected by ELISA. Transcriptomic features of aaRS-stimulated macrophages were examined using RNA-sequencing. Serum and synovial fluid (SF) aaRS levels in patients with RA were assessed using ELISA. Peptidyl arginine deiminase (PAD) 4 release from macrophages stimulated with aaRSs was detected by ELISA. Citrullination of aaRSs by themselves was examined by immunoprecipitation and western blotting. Furthermore, aaRS inhibitory peptides were used for inhibition of arthritis in two mouse RA models, collagen-induced arthritis and collagen antibody-induced arthritis.
RESULTS
All 20 aaRSs functioned as alarmin; they induced pro-inflammatory cytokines through the CD14-MD2-TLR4 axis. Stimulation of macrophages with aaRSs displayed persistent innate inflammatory responses. Serum and SF levels of many aaRSs increased in patients with RA compared with control subjects. Furthermore, aaRSs released PAD4 from living macrophages, leading to their citrullination. We demonstrate that aaRS inhibitory peptides suppress cytokine production and PAD4 release by aaRSs and alleviate arthritic symptoms in a mouse RA model.
CONCLUSIONS
Our findings uncovered the significant role of aaRSs as a novel alarmin in RA pathogenesis, indicating that their blocking agents are potent antirheumatic drugs.
Topics: Animals; Mice; Alarmins; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Cytokines; Disease Models, Animal; Fibroblasts; Inflammation; Synovial Fluid; Humans
PubMed: 37400117
DOI: 10.1136/ard-2023-224055 -
Macrophages in the synovial lining niche initiate neutrophil recruitment and articular inflammation.The Journal of Experimental Medicine Aug 2023The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In...
The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins with the activation of lining macrophages. We show that lining, but not sublining macrophages phagocytose immune complexes containing the model antigen. Using the antigen-induced arthritis (AIA) model, we demonstrate that on recognition of antigen-antibody complexes, lining macrophages undergo significant activation, which is dependent on interferon regulatory factor 5 (IRF5), and produce chemokines, most notably CXCL1. Consequently, at the onset of inflammation, neutrophils are preferentially recruited in the vicinity of antigen-laden macrophages in the synovial lining niche. As inflammation progresses, neutrophils disperse across the whole synovium and form swarms in synovial sublining during resolution. Our study alters the paradigm of lining macrophages as immunosuppressive cells to important instigators of synovial inflammation.
Topics: Humans; Neutrophil Infiltration; Arthritis; Macrophages; Synovial Membrane; Inflammation; Antigens
PubMed: 37115585
DOI: 10.1084/jem.20220595 -
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 -
Biomedicine & Pharmacotherapy =... Sep 2023The manipulation of macrophage recruitment and their shift in the M1/M2 ratio is a promising approach to mitigate osteoarthritis (OA). Nevertheless, the current clinical...
AIMS
The manipulation of macrophage recruitment and their shift in the M1/M2 ratio is a promising approach to mitigate osteoarthritis (OA). Nevertheless, the current clinical medication available for OA is only palliative and may result in undesirable outcomes. Hence, it is urgent to explore alternative disease-modifying drug supplement that are both safer and more effective in OA treatment, like probiotic and probiotic-derived membrane vesicles.
METHODS
The synovial inflammation and cartilage damage in collagenase-induced OA (CIOA) mice were observed using haematoxylin and eosin, saffron O-solid green and immunohistochemical staining. Bipedal balance test and open field test were conducted to determine the effectiveness of L. johnsonii-derived membrane vesicles (LJ-MVs) in reducing joint pain of CIOA mice. Additionally, Transwell, western blot, and immunological testing were used to examine the effect of LJ-MVs on macrophage migration and reprogramming. Furthermore, a 4D label-free proteomic analysis of LJ-MVs and their parent bacterium was performed, and the glutamine synthetase (GS)/mTORC1 axis in macrophage was verified by western blot.
RESULTS
L. johnsonii and its membrane vesicles, LJ-MVs, exhibit a novel ability to mitigate inflammation, cartilage damage, and pain associated with OA. This is achieved by their ability to impede macrophage migration, M1-like polarization, and inflammatory mediators secretion, while simultaneously promoting the M2/M1 ratio in synovial macrophages. The mechanism underlying this effect involves the modulation of macrophage GS/mTORC1 pathway, at least partially.
SIGNIFICANCE
Owing to their probiotic derivation, LJ-MVs will be a more dependable and potent disease-modifying drugs for the prevention and therapy of OA in the long run.
Topics: Mice; Animals; Lactobacillus johnsonii; Glutamate-Ammonia Ligase; Synovial Membrane; Mechanistic Target of Rapamycin Complex 1; Proteomics; Osteoarthritis; Macrophages; Inflammation
PubMed: 37499456
DOI: 10.1016/j.biopha.2023.115204 -
World Journal of Orthopedics Sep 2023Current research lacks a model of knee extension contracture in rats.
BACKGROUND
Current research lacks a model of knee extension contracture in rats.
AIM
To elucidate the formation process of knee extension contracture.
METHODS
We developed a rat model using an aluminum external fixator. Sixty male Sprague-Dawley rats with mature bones were divided into the control group ( = 6) and groups that had the left knee immobilized with an aluminum external fixator for 1, 2, and 3 d, and 1, 2, 3, 4, 6, and 8 wk ( = 6 in each group). The passive extension range of motion, histology, and expression of fibrosis-related proteins were compared between the control group and the immobilization groups.
RESULTS
Myogenic contracture progressed very quickly during the initial 2 wk of immobilization. After 2 wk, the contracture gradually changed from myogenic to arthrogenic. The arthrogenic contracture progressed slowly during the 1 week, rapidly progressed until the 3 week, and then showed a steady progression until the 4 week. Histological analyses confirmed that the anterior joint capsule of the extended fixed knee became increasingly thicker over time. Correspondingly, the level of transforming growth factor beta 1 (TGF-β1) and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2) in the anterior joint capsule also increased with the immobilization time. Over time, the cross-sectional area of muscle fibers gradually decreased, while the amount of intermuscular collagen and TGF-β1, p-Smad2, and p-Smad3 was increased. Unexpectedly, the amount of intermuscular collagen and TGF-β1, p-Smad2, and p-Smad3 was decreased during the late stage of immobilization (6-8 wk). The myogenic contracture was stabilized after 2 wk of immobilization, whereas the arthrogenic contracture was stabilized after 3 wk of immobilization and completely stable in 4 wk.
CONCLUSION
This rat model may be a useful tool to study the etiology of joint contracture and establish therapeutic approaches.
PubMed: 37744718
DOI: 10.5312/wjo.v14.i9.669