Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Lefèvre, Stephanie; Knedla, Anette; Tennie, Christoph; Kampmann, Andreas; Wunrau, C; Dinser, Robert; Korb, Adelheid; Schnäker, Eva Maria; Tarner, Ingo H.; Robbins, Paul D.; Evans, Christopher H.; Stürz, H.; Steinmeyer, Jürgen; Schölmerich, Jürgen; Pap, Thomas; Müller‐Ladner, Ulf; Neumann, Elena

doi:10.1038/nm.2050

Cited by 561 publications

(487 citation statements)

References 47 publications

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“…In RA, joints are affected progressively over decades. Although this progression may be the result of joints being targeted by the circulating pool of autoreactive T cells, recent data suggest that transmigration of RA synovial fibroblasts via the blood may be, at least in part, responsible for spreading disease into unaffected joint tissue (8).…”

Section: Conclusion Circulating Fibrocytes Migrate To Joints and Infmentioning

confidence: 99%

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/ chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA.Methods. Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680.Results. The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation.Conclusion. Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.

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Section: Conclusion Circulating Fibrocytes Migrate To Joints and Infmentioning

confidence: 99%

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

Arthritis & Rheumatism

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“…MLSs phagocytose cell debris and wastes in the synovial fluid and possess professional antigen presentation capacity (2,3). FLSs of RA patients (RA-FLSs) can migrate/attach to cartilage and bone and invade the local environment (2,4). Moreover, RA-FLSs proliferate abnormally and exhibit several oncogenes or tumor suppressor genes, including H-ras and p53, harboring somatic mutations (5,6).…”

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confidence: 99%

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

You

Yoo²,

Choi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)–stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS–dominant (invasive), and RA-SM–dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix–loop–helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

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“…First described by Geiler et al and Pap et al, cotransplantation of RA synovial tissue or, as more frequently applied, of RA synovial fibroblasts (RASFs) with pieces of cartilage into SCID mice is used to study the capacity of the fibroblast-like synoviocytes to degrade matrix and invade the cartilage (6,7). A recent elegant article reported the migratory and destructive characteristics of RASFs traveling from the transplantation site to healthy cartilage in the contralateral flank (8). Obviously, this cartilage invasion model is limited to one specific cell type as a major key player in the arthritis process, focusing completely on the fibroblast and its destructive mediators and excluding the potential contribution of other cell types to the degradation of cartilage.…”

mentioning

confidence: 99%

T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3‐rich synovium lacks response to CTLA‐4ig but is successfully treated by interleukin‐17 neutralization

Koenders¹,

Marijnissen²,

Joosten³

et al. 2012

Arthritis & Rheumatism

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Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Cited by 561 publications

References 47 publications

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3‐rich synovium lacks response to CTLA‐4ig but is successfully treated by interleukin‐17 neutralization

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