The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis.
TL;DR: The cytokine network in OA is put in the context of cells involved in this degenerative joint disease and the possibilities for further implementation of new therapeutic strategies are pointed.
Abstract: Osteoarthritis (OA) is the most common chronic disease of human joints. The basis of pathologic changes involves all the tissues forming the joint; already, at an early stage, it has the nature of inflammation with varying degrees of severity. An analysis of the complex relationships indicates that the processes taking place inside the joint are not merely a set that (seemingly) only includes catabolic effects. Apart from them, anti-inflammatory anabolic processes also occur continually. These phenomena are driven by various mediators, of which the key role is attributed to the interactions within the cytokine network. The most important group controlling the disease seems to be inflammatory cytokines, including IL-1β, TNFα, IL-6, IL-15, IL-17, and IL-18. The second group with antagonistic effect is formed by cytokines known as anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA with respect to inter- and intracellular signaling pathways is still under investigation. This paper summarizes the current state of knowledge. The cytokine network in OA is put in the context of cells involved in this degenerative joint disease. The possibilities for further implementation of new therapeutic strategies in OA are also pointed.
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TL;DR: Current knowledge on the prevalence of synovial inflammation in OA and its role in symptoms and structural progression is reviewed, and lessons learnt from targeting synovitis therapeutically are explored.
Abstract: Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically.
579 citations
Cites background from "The role of inflammatory and anti-i..."
...[16] recently described in detail the mediating cytokines and their signalling pathways that are up-regulated in OA and most often have catabolic (i....
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...They are elevated in OA synovial fluid, synovial membrane, cartilage and subchondral bone and, in the course of OA, have synergistic effects on signalling pathways that increase inflammation and cartilage degradation [16]....
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...Some cytokines (such as IL-4, IL-10 and IL-13) have anti-inflammatory and sometimes anabolic effects, and may modulate an inflammatory response and slow progression of OA [16]....
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TL;DR: The data show that the history of an ACL injury, including trauma and reconstruction, has a significant impact on levels of IL-6, IL-8, and IL-10 in synovial fluid but does not affect levels of TNF-α andIL-1β.
Abstract: Anterior cruciate ligament (ACL) reconstruction restores knee stability but does not reduce the incidence of posttraumatic osteoarthritis induced by inflammatory cytokines. The aim of this research was to longitudinally measure IL-1β, IL-6, IL-8, IL-10, and TNF-α levels in patients subjected to ACL reconstruction using bone-patellar tendon-bone graft. Synovial fluid was collected within 24–72 hours of ACL rupture (acute), 1 month after injury immediately prior to surgery (presurgery), and 1 month thereafter (postsurgery). For comparison, a “control” group consisted of individuals presenting chronic ACL tears. Our results indicate that levels of IL-6, IL-8, and IL-10 vary significantly over time in reconstruction patients. In the acute phase, the levels of these cytokines in reconstruction patients were significantly greater than those in controls. In the presurgery phase, cytokine levels in reconstruction patients were reduced and comparable with those in controls. Finally, cytokine levels increased again with respect to control group in the postsurgery phase. The levels of IL-1β and TNF-α showed no temporal variation. Our data show that the history of an ACL injury, including trauma and reconstruction, has a significant impact on levels of IL-6, IL-8, and IL-10 in synovial fluid but does not affect levels of TNF-α and IL-1β.
422 citations
TL;DR: The roles of NF-κB in OA chondrocytes and related signaling pathways are discussed to better understand pathological cartilage remodeling and provide potential therapeutic targets that can interfere with NF-σB signaling for OA treatment.
Abstract: Osteoarthritis (OA) is a type of joint disease associated with wear and tear, inflammation, and aging. Mechanical stress along with synovial inflammation promotes the degradation of the extracellular matrix in the cartilage, leading to the breakdown of joint cartilage. The nuclear factor-kappaB (NF-κB) transcription factor has long been recognized as a disease-contributing factor and, thus, has become a therapeutic target for OA. Because NF-κB is a versatile and multi-functional transcription factor involved in various biological processes, a comprehensive understanding of the functions or regulation of NF-κB in the OA pathology will aid in the development of targeted therapeutic strategies to protect the cartilage from OA damage and reduce the risk of potential side-effects. In this review, we discuss the roles of NF-κB in OA chondrocytes and related signaling pathways, including recent findings, to better understand pathological cartilage remodeling and provide potential therapeutic targets that can interfere with NF-κB signaling for OA treatment.
274 citations
Cites background from "The role of inflammatory and anti-i..."
...Inflammatory cytokines derived from the OA synovium or damaged cartilage are well-known to cause catabolic gene induction in chondrocytes through mechanisms involving NF-κB activation [142,143]....
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TL;DR: The important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided.
Abstract: Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided.
263 citations
Cites background from "The role of inflammatory and anti-i..."
...In addition, there was precious little evidence that inflammatory cytokines such as prostaglandins, TNF-a, interleukin-1, interleukin-6 and nitric oxide, are important in vivo even though they are potent inducers in vitro [33]....
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TL;DR: This review is aimed at summarizing the previous studies highlighting the involvement of inflammation in the pathogenesis of osteoarthritis, a common chronic debilitating joint disease mainly affecting the elderly.
Abstract: A joint is the point of connection between two bones in our body. Inflammation of the joint leads to several diseases, including osteoarthritis, which is the concern of this review. Osteoarthritis is a common chronic debilitating joint disease mainly affecting the elderly. Several studies showed that inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. This stimulates the release of early-stage inflammatory cytokines like interleukin-1 beta (IL-1β), which in turn induces the activation of signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinase (MAPK). These events, in turn, generate more inflammatory molecules. Subsequently, collagenase like matrix metalloproteinases-13 (MMP-13) will degrade the extracellular matrix. As a result, anatomical and physiological functions of the joint are altered. This review is aimed at summarizing the previous studies highlighting the involvement of inflammation in the pathogenesis of osteoarthritis.
229 citations
Cites background from "The role of inflammatory and anti-i..."
...alter cell signaling pathways, gene expression, and behavior of joint tissue [11]....
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References
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University of Miami1, New York University2, Stanford University3, University of Michigan4, George Washington University5, Indiana University6, University of Pittsburgh7, Queen's University8, North Shore-LIJ Health System9, Johns Hopkins University10, SUNY Downstate Medical Center11, University of Alabama at Birmingham12, University of Florida13, Harvard University14, Boston University15, Case Western Reserve University16, Washington University in St. Louis17, Menorah Medical Center18, Stony Brook University19, University of Kansas20
TL;DR: Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes and these proposed criteria utilize classification trees, or algorithms.
Abstract: For the purposes of classification, it should be specified whether osteoarthritis (OA) of the knee is of unknown origin (idiopathic, primary) or is related to a known medical condition or event (secondary). Clinical criteria for the classification of idiopathic OA of the knee were developed through a multicenter study group. Comparison diagnoses included rheumatoid arthritis and other painful conditions of the knee, exclusive of referred or para-articular pain. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes. In contrast to prior criteria, these proposed criteria utilize classification trees, or algorithms.
6,160 citations
TL;DR: Transforming growth factor-β (TGF-β) proteins regulate cell function, and have key roles in development and carcinogenesis, and combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smadracing proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF- β family responses.
Abstract: Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses
4,690 citations
TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...
4,548 citations
"The role of inflammatory and anti-i..." refers background in this paper
...The source of IL-17 ismainly stimulated CD4 T cells and mast cells that infiltrate the synovialmembrane and the entire joint through blood vessels [138–141]....
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TL;DR: The cloning of a recently identified IFN-γ-inducing factor (IGIF) that augments natural killer activity in spleen cells and may be involved in the development of Thl cells and also in mechanisms of tissue injury in inflammatory reactions is reported.
Abstract: The mechanism underlying the differentiation of CD4+ T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood, and hitherto unidentified cytokines may be required for the functional maturation of these cells. Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.
2,526 citations
TL;DR: TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal fails to be activated, and the cell survives.
2,478 citations