The role of synovial macrophages and macrophage‐produced mediators in driving inflammatory and destructive responses in osteoarthritis

Bondeson, Jan; Blom, A.B.; Wainwright, S.D.; Hughes, Claire E.; Caterson, Bruce; Berg, Wim B. van den

doi:10.1002/art.27290

Cited by 446 publications

(446 citation statements)

References 73 publications

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“…6-10 To our surprise, however, synovial fibroblasts produced PGE2, IL-6 and IL-8 without the stimulation of IL-1β and TNF-α, which are produced by synovial macrophages. Undoubtedly, IL-1β and TNF-α, produced by synovial macrophages, are considered to be key factors for OA development through the production of PGE2, MMPs, and ADAMTSs by synovial fibroblasts and chondrocytes.…”

Section: Discussionmentioning

confidence: 63%

“…2-6 Synovial fibroblasts and macrophages, as well as chondrocytes, play an important role in OA development through synovitis, and synovial macrophages are considered to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). 6-10 These cytokines stimulate synovial fibroblasts and chondrocytes to produce other cytokines, such as IL-6 and IL-8, and several enzymes, such as matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs). These enzymes sever type II collagen and proteoglycan, the principal components of the extracellular matrix of articular cartilage.…”

Section: Introductionmentioning

confidence: 99%

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Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1β and TNF-α

Shimomura

Kanamoto

Kita

et al. 2014

Bone & Joint Research

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ObjectiveExcessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model.MethodHuman synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), IL-6, IL-8 and COX-2 were measured.ResultsThe concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1β and TNF-α were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed.ConclusionThese results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA.Cite this article: Bone Joint Res 2014;3:280–8.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1β and TNF-α

Shimomura

Kanamoto

Kita

et al. 2014

Bone & Joint Research

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“…The relationship of synovial hyperplasia to OA‐related chondropathy has been noted previously 22, 44, with activated synovial macrophages playing a key role in the inflammatory process 21, leading to expansion of the lining cell layer with occasional infiltration by lymphocytes and monocytes 45. These synovial events had not been previously characterized in the context of diabetes and/or obesity.…”

Section: Discussionmentioning

confidence: 84%

Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

Hamada

Maynard

Schott

et al. 2016

Arthritis & Rheumatology

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ObjectiveObesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity‐associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance.MethodsThe effects of TNF and insulin on catabolic gene expression were determined in fibroblast‐like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high‐fat (HF) diet–fed obese mice with type 2 DM and TNF‐knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM.ResultsInsulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose‐dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF‐knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin‐dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM.ConclusionTNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin resistance in patients with type 2 DM may impair this protective effect and promote the progression of OA.

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“…Several studies show a distinct connection between the evolution of tibiofemoral cartilage damage and the occurrence of activated synovial macrophages [28,29]. Discharged inflammatory factors such as proinflammatory cytokines are essential mediators of the disturbed metabolism and enhanced catabolism of joint tissue involved in OA [6]].…”

Section: Discussionmentioning

confidence: 99%

Activation of a7 Nicotinic Acetylcholine Receptors Prevents Monosodium Iodoacetate-Induced Osteoarthritis in Rats

Liu

Song

et al. 2015

Cell Physiol Biochem

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Background/Aims: Although some evidence suggests that the prevalence of osteoarthritis (OA) is lower in smokers compared to nonsmokers, the mechanisms of nicotine-induced protection remain unclear. Stimulation of the a7 nicotinic acetylcholine receptor (a7-nAChR) appears to be a critical mechanism underlying the anti-inflammatory potential of cholinergic agonists in immune cells. The inhibition of secreted inflammatory molecules and the subsequent inflammatory processes have been proposed as a novel strategy for the treatment of OA. The objective of the present study was to determine whether nicotine-induced protection in a monosodium iodoacetate (MIA) rat model of OA occurs via a7-nAChR-mediated inhibition of chondrocytes. Methods: Both in vivo (MIA) and in vitro (MIA; Interleukin-1ß, IL-1ß) models of OA were used to investigate the roles and the possible mechanisms whereby a7-nAChRs protect against knee joint degradation. Multiple experimental approaches, including macroscopic, histological analysis, chondrocyte cell cultures, confocal microscopy, and western blotting, were employed to elucidate the mechanisms of a7-nAChR-mediated protection. Results: Systemic administration of nicotine alleviated MIA-induced joint degradation. The protective effects of nicotine were abolished by administration of the a7-nAChR-selective antagonist methyllycaconitine (MLA). In primary cultured rat chondrocytes, pretreatment with nicotine suppressed both p38, extracellular regulated kinase (Erk) 1/2 and c-Jun-N-terminal kinase (JNK) mitogen-activated protein kinases (MAPK) phosphorylation and phosphorylated nuclear factor-kappa B (NF-κB) p65 activation induced by MIA- or IL-1ß, and these effects were also reversed by MLA. Conclusion: Taken together, our results suggest that activation a7-nAChRs is an important mechanism underlying the protective effects of nicotine.

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The role of synovial macrophages and macrophage‐produced mediators in driving inflammatory and destructive responses in osteoarthritis

Cited by 446 publications

References 73 publications

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1β and TNF-α

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1β and TNF-α

Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

Activation of a7 Nicotinic Acetylcholine Receptors Prevents Monosodium Iodoacetate-Induced Osteoarthritis in Rats

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