PURPOSE OF REVIEWInflammatory changes in joint tissues can be detected by modern imaging techniques in osteoarthritis patients, but may be clinically subtle compared with many other types of ...arthritis. These changes associate with disease progression and clinical severity, and many inflammatory mediators may have biomarker utility. Moreover, a number of inflammatory mechanisms play a role in animal models of disease, but it is still not clear which mechanisms predominate and might be therapeutically manipulated most effectively. This review highlights specific examples of recent advances published in the past 18 months that have advanced this field.
RECENT FINDINGSClinical investigators now show that synovial inflammation is associated with pain sensitization, and similar to knee osteoarthritis, is a common and important feature of hand osteoarthritis. In addition, recent advances in basic studies demonstrate inflammatory markers and mechanisms related to leukocyte activity, innate immune mechanisms, and the chondrocyte-intrinsic inflammatory response that might provide better opportunities for early detection, prognosis, or therapeutic intervention.
SUMMARYInflammation plays a central role in osteoarthritis pathogenesis, but additional translational work in this field is necessary, as are more clinical trials of anti-inflammatory approaches.
Abstract Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but there is increasing recognition that OA affects all of the joint tissues, ...including the synovium (SM). Under normal physiological conditions the synovial lining consists of a thin layer of cells with phenotypic features of macrophages and fibroblasts. These cells and the underlying vascularized connective tissue stroma form a complex structure that is an important source of synovial fluid (SF) components that are essential for normal cartilage and joint function. The histological changes observed in the SM in OA generally include features indicative of an inflammatory “synovitis”; specifically they encompass a range of abnormalities, such as synovial lining hyperplasia, infiltration of macrophages and lymphocytes, neoangiogenesis and fibrosis. The pattern of synovial reaction varies with disease duration and associated metabolic and structural changes in other joint tissues. Imaging modalities including magnetic resonance (MRI) and ultrasound (US) have proved useful in detecting and quantifying synovial abnormalities, but individual studies have varied in their methods of evaluation. Despite these differences, most studies have concluded that the presence of synovitis in OA is associated with more severe pain and joint dysfunction. In addition, synovitis may be predictive of faster rates of cartilage loss in certain patient populations. Recent studies have provided insights into the pathogenic mechanisms underlying the development of synovitis in OA. Available evidence suggests that the inflammatory process involves engagement of Toll-like receptors and activation of the complement cascade by degradation products of extracellular matrices of cartilage and other joint tissues. The ensuing synovial reaction can lead to synthesis and release of a wide variety of cytokines and chemokines. Some of these inflammatory mediators are detected in joint tissues and SF in OA and have catabolic effects on chondrocytes. These inflammatory mediators represent potential targets for therapeutic interventions designed to reduce both symptoms and structural joint damage in OA. This article is part of a Special Issue entitled “Osteoarthritis”.
Although osteoarthritis (OA) was historically referred to as the non-inflammatory arthritis, it is now considered a condition involving persistent low-grade inflammation and activation of innate ...inflammatory pathways. Synovitis increases the risk of OA onset and progression and involves the recruitment of monocytes, lymphocytes, and other leukocytes. In particular, macrophages are important mediators of synovial inflammatory activity and pathologic cartilage and bone responses that are characteristic of OA. Advances in understanding how damage-associated molecular patterns (DAMPs) trigger monocyte/macrophage recruitment and activation in joints provide opportunities for disease-modifying therapies. However, the complexity and plasticity of macrophage phenotypes that exist
in vivo
have thus far prevented the successful development of macrophage-targeted treatments. Current studies show that synovial macrophages are derived from distinct cellular lineages, which correspond to unique functional roles for maintaining joint homeostasis. An improved understanding of the etiology of synovial inflammation in specific OA-subtypes, such as with obesity or genetic risk, is a potential strategy for developing patient selection criteria for future precision therapies.
Summary Inflammation is a variable feature of osteoarthritis (OA), associated with joint symptoms and progression of disease. Signs of inflammation can be observed in joint fluids and tissues from ...patients with joint injuries at risk for development of post-traumatic osteoarthritis (PTOA). Furthermore, inflammatory mechanisms are hypothesized to contribute to the risk of OA development and progression after injury. Animal models of PTOA have been instrumental in understanding factors and mechanisms involved in chronic progressive cartilage degradation observed after a predisposing injury. Specific aspects of inflammation observed in humans, including cytokine and chemokine production, synovial reaction, cellular infiltration and inflammatory pathway activation, are also observed in models of PTOA. Many of these models are now being utilized to understand the impact of post-injury inflammatory response on PTOA development and progression, including risk of progressive cartilage degeneration and development of chronic symptoms post-injury. As evidenced from these models, a vigorous inflammatory response occurs very early after joint injury but is then sustained at a lower level at the later phases. This early inflammatory response contributes to the development of PTOA features including cartilage erosion and is potentially modifiable, but specific mediators may also play a role in tissue repair. Although the optimal approach and timing of anti-inflammatory interventions after joint injury are yet to be determined, this body of work should provide hope for the future of disease modification tin PTOA.
CD14 is a monocyte/macrophage pattern-recognition receptor that modulates innate inflammatory signaling. Soluble CD14 levels in knee OA synovial fluids are associated with symptoms and progression of ...disease. Here we investigate the role of this receptor in development of OA using a murine joint injury model of disease.
10-week-old Male C57BL/6 (WT) and CD14-deficient (CD14-/-) mice underwent destabilization of the medial meniscus (DMM) surgery to induce OA. Joint histopathology was used to examine cartilage damage, and microCT to evaluate subchondral bone (SCB) remodeling at 6 and 19 weeks after surgery. Synovial and fat pad expression of macrophage markers (F4/80, CD11c, CD68, iNOS, CCR7, CD163 and CD206) was assessed by flow cytometry and droplet digital (dd)PCR. Changes in locomotive activity indicative of joint pain were evaluated longitudinally up to 16 weeks by automated behavioral analysis.
Early cartilage damage scores 6 weeks post-DMM were similar in both strains (Mean score ±SEM WT: 4.667±1.38, CD14-/-: 4.6±0.6), but at 19 weeks were less severe in CD14-/- (6.0±0.46) than in WT mice (13.44±2.5, p = 0.0002). CD14-/- mice were protected from both age-related and post-surgical changes in SCB mineral density and trabecular thickness. In addition, CD14-/- mice were protected from decreases in climbing activity (p = 0.015 vs. WT, 8 weeks) observed after DMM. Changes in synovial/fat pad expression of CCR7, a marker of M1 macrophages, were slightly reduced post-DMM in the absence of CD14, while expression of CD68 (pan-macrophage marker) and CD163 (M2 marker) were unchanged.
CD14 plays an important role in progression of structural and functional features of OA in the DMM model, and may provide a new target for therapeutic development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now ...widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.
Fibroses are disorders linked to persistence of myofibroblasts due to biochemical (e.g., Transforming growth factor-β) and biophysical cues (e.g., a stiff microenvironment). In the context of ...osteoarthritis, fibrotic changes in the joint-lining synovium have been linked with disease progression. The objective of this study was to probe synovial fibroblast mechanobiology and how essential functions (i.e., lubrication) are altered in fibrotic environments.
Both ex vivo and in vitro synovium models were assessed for fibrotic and lubrication biomarkers to better understand the role of mechanobiology and lubrication. Additionally, in vitro, work on small molecules targeting mechanobiology was assessed.
Our results indicated that modulating mechanobiology could rescue the fibrotic phenotype instigated by stiffening microenvironment that resulted in altered lubricant expression. A small molecule therapeutic, fasudil, blocked ROCK-mediated contractility and this inhibition of the fibrotic mechano-response of synovial fibroblasts restored proper lubrication function, providing insight into mechanisms of disease progression as well as a new avenue for therapeutic development.
This study identifies synovial fibrosis as a condition that potentially has joint-wide deficits through inhibiting lubrication. Additionally, modulating mechanobiology (i.e., ROCK-mediated contractility) may pose a potential target for small molecule therapies that can be delivered to the joint space.
Applied Biological Sciences.
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