Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture

Kiener, Hans P.; Watts, Gerald F.; Cui, Yang; Wright, John; Thornhill, Thomas S.; Sköld, Markus; Behar, Samuel M.; Niederreiter, Birgit; Lu, Jun; Cernadas, Manuela; Coyle, Anthony J.; Sims, Gary P.; Smolen, Josef S.; Warman, Matthew L.; Brenner, Michael B.; Lee, David M.

doi:10.1002/art.27285

Cited by 103 publications

(102 citation statements)

References 50 publications

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“…5A, upper). These findings were consistent with reports in the literature (25,29) and validated the assay response. Conversely, RA-FLSs transfected with shRNA for ITGA9 did not condense into lining-like architecture nor did it exhibit a hyperplastic response to PDGF (Fig.…”

Section: Role Of A9 Is Indispensable For Ra-fls Responses To Inflammasupporting

confidence: 93%

“…Recently, a unique three-dimensional (3D) culture system of RA-FLSs has been reported. In this system, isolated RAFLSs not only establish hyperplastic lining-like aggressive cell assembly but also respond to TNF-a to produce proinflammatory cytokines, chemokines, and MMPs (25). The 3D-culture system thus appears to provide an in vitro model relevant to synovial hyperplasia in vivo and may be a powerful tool to analyze the abnormal behaviors intrinsic to RA-FLSs.…”

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confidence: 99%

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Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Emori

Hirose

Ise

et al. 2017

The Journal of Immunology

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Despite advances in the treatment of rheumatoid arthritis (RA), currently approved medications can have significant side effects due to their direct immunosuppressive activities. Additionally, current therapies do not address residual synovial inflammation. In this study, we evaluated the role of integrin α9 and its ligand, tenascin-C (Tn-C), on the proliferative and inflammatory response of fibroblast-like synoviocytes (FLSs) from RA patients grown in three-dimensional (3D)–micromass culture. FLSs from osteoarthritis patients, when grown in the 3D-culture system, formed self-directed lining-like structures, whereas FLSs from RA tissues (RA-FLSs) developed an abnormal structure of condensed cellular accumulation reflective of the pathogenic features of RA synovial tissues. Additionally, RA-FLSs grown in 3D culture showed autonomous production of proinflammatory mediators. Predominant expression of α9 and Tn-C was observed in the condensed lining, and knockdown of these molecules abrogated the abnormal lining-like structure formation and suppressed the spontaneous expression of matrix metalloproteinases, IL-6, TNFSF11/RANKL, and cadherin-11. Disruption of α9 also inhibited expression of Tn-C, suggesting existence of a positive feedback loop in which the engagement of α9 with Tn-C self-amplifies its own signaling and promotes progression of synovial hyperplasia. Depletion of α9 also suppressed the platelet-derived growth factor–induced hyperplastic response of RA-FLSs and blunted the TNF-α–induced expression of matrix metalloproteinases and IL-6. Finally, α9-blocking Ab also suppressed the formation of the condensed cellular lining by RA-FLSs in 3D cultures in a concentration-related manner. This study demonstrates the central role of α9 in pathogenic behaviors of RA-FLSs and highlights the potential of α9-blocking agents as a nonimmunosuppressive treatment for RA-associated synovitis.

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Section: Role Of A9 Is Indispensable For Ra-fls Responses To Inflammasupporting

confidence: 93%

mentioning

confidence: 99%

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Emori

Hirose

Ise

et al. 2017

The Journal of Immunology

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“…Previous work on synovial fibroblast-macrophage interactions in the absence of inflammatory factors showed that these cells interact (“cocompact”) to form a lining-like structure that resembles that of the synovium, supporting the biological relevance of the co-culture approach (49, 50). Experiments using this system showed that synovial fibroblasts promote macrophage survival, and that stimulation with TNF results in lining hyperplasia and inflammatory mediator production (49); however, the effects of cell crosstalk in an inflammatory setting were not examined. Our findings extend this approach to show substantial crossregulation between these two cell types in the setting of inflammation as modelled by TNF stimulation.…”

Section: Discussionmentioning

confidence: 73%

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Donlin

Jayatilleke

Γιαννοπούλου³

et al. 2014

The Journal of Immunology

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Mesenchymal stromal cells have emerged as powerful modulators of the immune system. Here we explored how the human macrophage response to tumor necrosis factor (TNF) is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. We found that synovial fibroblasts strongly suppressed TNF-mediated induction of an interferon (IFN)-β autocrine loop and downstream expression of IFN-stimulated genes (ISGs), including chemokines CXCL9 and CXCL10 that are characteristic of classical macrophage activation. TNF induced the production of soluble synovial fibroblast factors that suppressed the macrophage production of IFN-β, and cooperated with TNF to limit the responsiveness of macrophages to IFN-β by suppressing activation of Jak-STAT signalling. Genome-wide transcriptome analysis showed that co-cultured synovial fibroblasts modulate the expression of approximately one third of TNF-regulated genes in macrophages, including genes in pathways important for macrophage survival and polarization towards an alternatively activated phenotype. Pathway analysis revealed that gene expression programs regulated by synovial fibroblasts in our co-culture system were also regulated in rheumatoid arthritis (RA) synovial macrophages, suggesting that these fibroblast-mediated changes may contribute to RA pathogenesis. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.

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“…At the cellular level, autoantibodies and autoreactive T cells are believed to be responsible for initiation of RA (4, 5), while increasing evidence suggests synovial fibroblasts (SFs) – the resident fibroblast-like cells of the synovial membrane – play a critical role in perpetuating disease (6, 7). In healthy tissue SFs form a one to two cell-thick layer at the lining of the synovium, function to maintain the synovial membrane architecture, and produce lubricating molecules for the joint (8, 9). In RA; however, SFs have been described as transformed cells, in which they display morphologic features similar to cancer cells such as hyperplasia and resistance to apoptosis (6, 10).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

et al. 2018

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Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging, in part because of the complexities and interconnected nature of intracellular signaling networks, which complicate the effects of pharmacological interventions. Here, we characterized the signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. For example, p38 inhibitors, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NFκB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. CREB, a transcription factor that functions in part within a negative feedback loop in MAPK signaling, emerged as a key regulator of this context-dependence. CREB activation was induced predominately by p38 in response to inflammatory stimuli but by MEK in response to mitogenic stimuli; the effects of drugs targeting p38 or MEK were therefore markedly different in SFs cultured in mitogenic or inflammatory conditions. Together these findings illustrate how stimulatory context can alter pathway cross-talk even for a fixed network topology, suggest cross-talk by p38 in inflammatory contexts limited the benefit of p38 inhibitors in RA, and furthermore demonstrate the need for careful consideration of p38-targeted drugs in inflammation-related disorders.

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Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture

Abstract: The synovium is a complex, specialized tissue composed of heterogeneous cellular populations, acel-

Cited by 103 publications

References 50 publications

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition

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