Are fibroblasts involved in joint destruction?

Pap, Thomas; Meinecke, Ingmar; Müller‐Ladner, Ulf

doi:10.1136/ard.2005.042424

Cited by 56 publications

(55 citation statements)

References 22 publications

(16 reference statements)

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“…In particular, the important role of macrophages and lymphocytes in this process has long been established (13,14). However, the synovial fibroblasts (SF) in the most superficial lining layer of the hyperplastic RA synovium and in direct contact to cartilage structures play a crucial role in joint damage and the propagation of inflammation (3,15,16). It could be shown that isolated RA-SF, implanted with normal human cartilage under the renal capsule of SCID mice, invade the implants; even in the absence of lymphocytes and macrophages, they behave like SF in a rheumatic joint (17).…”

Section: Discussionmentioning

confidence: 99%

Characterization of fibroblasts responsible for cartilage destruction in arthritis

et al. 2008

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In the pathogenesis of rheumatoid arthritis (RA), synovial fibroblasts (SF) play a key role as they secrete distinct patterns of cytokines and express variable levels of costimulatory and adhesion molecules. The murine fibroblast cell line LS48 has been shown to be invasive in the cartilage destruction models in vivo and in vitro. The purpose of this study was to examine in detail the LS48 phenotype, to obtain a better understanding of the SF-mediated cartilage destruction in RA. The destructive fibroblasts line LS48 and the nondestructive 3T3 cells were cultured and characterized with slide-based and flow cytometry, using antibodies against several adhesion molecules, immunological acting molecules, and marker proteins. The invasive LS48 fibroblasts are characterized by significantly higher expression of adhesion molecules such as CD47 (IAP), CD51 (integrin aV), CD61 (GPIIIa), and CD147 (EMMPRIN), and immunological acting molecules such as CD40 (Bp50), CD55 (DAF), and TLR-2. The results from the slide-based and flow cytometry analyses were exactly the same, except for the selected CD147 and TLR-2. This study demonstrated that the destructive fibroblast cell line LS48 has the characteristics of RA SFs. The high expression of specific costimulatory and adhesion molecules underlines the aberrant phenotype of these cells when compared with noninvasive fibroblasts. Furthermore, slide-based and flow cytometry complement each other in fibroblast phenotyping. Overall, this study shows that LS48 is an excellent tool to gain a deeper understanding of SF in RA. '

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Section: Discussionmentioning

confidence: 99%

Characterization of fibroblasts responsible for cartilage destruction in arthritis

et al. 2008

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“…The pathologic hallmark of RA is the formation of invasive pannus, the thickened layer of synovial tissue that erodes cartilage and bone. RA-FLSs intrinsically acquire an aggressive phenotype and become the spearhead of inflamed synovium mediating inflammation and destruction of the joint (2,29). They destroy bone and cartilage indirectly by releasing matrixdegrading enzymes, such as MMPs and cathepsins (30), and also directly invade adjacent structures even without the help of inflammatory cells (4,31).…”

Section: Discussionmentioning

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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“…RA synovial fibroblasts (RASF) are intrinsically activated and therefore invade into cartilage by excessive expression of matrix degrading enzymes such as matrix metalloproteinases (MMPs) MMP-1, 3, 9, 10 and 13 (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression

Maciejewska-Rodrigues¹,

Karouzakis²,

Strietholt³

et al. 2010

Journal of Autoimmunity

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The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyse whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1.In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 ± 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 ± 0.5% and globally by 73 ± 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58  7%) and protein levels (28 ± 6%), significantly reduced the invasiveness of RASF (from 34  9% to 2  2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 ± 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.

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Are fibroblasts involved in joint destruction?

Cited by 56 publications

References 22 publications

Characterization of fibroblasts responsible for cartilage destruction in arthritis

Characterization of fibroblasts responsible for cartilage destruction in arthritis

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

Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression

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