Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis

Derer, Anja; Böhm, Christina; Grötsch, Bettina; Grün, Joachim R.; Grützkau, Andreas; Stöck, Michael; Böhm, Sonja; Sehnert, Bettina; Gaipl, Udo S.; Schett, Georg; Hueber, Axel J.; David, Jean‐Pierre

doi:10.1136/annrheumdis-2014-205618

Cited by 18 publications

(14 citation statements)

References 52 publications

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“…AGTR2 inhibitors have been shown to ameliorate disease in a rodent model of arthritis as well as in ex vivo FLS cultures 37 . RPS6KA3 has also been shown to control hyperplasia of FLSs, and to impact the course of inflammatory arthritis in mice 38 . Each of these targets had been functionally validated in RA models in fewer than 3 papers and/or later than 2016, supporting the ability of Rosalind to identify under-explored yet promising opportunities.…”

Section: Resultsmentioning

confidence: 99%

Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs

Paliwal¹,

Giorgio

Neil³

et al. 2020

Sci Rep

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Incorrect drug target identification is a major obstacle in drug discovery. Only 15% of drugs advance from Phase II to approval, with ineffective targets accounting for over 50% of these failures1–3. Advances in data fusion and computational modeling have independently progressed towards addressing this issue. Here, we capitalize on both these approaches with Rosalind, a comprehensive gene prioritization method that combines heterogeneous knowledge graph construction with relational inference via tensor factorization to accurately predict disease-gene links. Rosalind demonstrates an increase in performance of 18%-50% over five comparable state-of-the-art algorithms. On historical data, Rosalind prospectively identifies 1 in 4 therapeutic relationships eventually proven true. Beyond efficacy, Rosalind is able to accurately predict clinical trial successes (75% recall at rank 200) and distinguish likely failures (74% recall at rank 200). Lastly, Rosalind predictions were experimentally tested in a patient-derived in-vitro assay for Rheumatoid arthritis (RA), which yielded 5 promising genes, one of which is unexplored in RA.

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Section: Resultsmentioning

confidence: 99%

Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs

Paliwal¹,

Giorgio

Neil³

et al. 2020

Sci Rep

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“…In a previous study, TNF-α stimulation was shown to increase PDGFR expression via MAPK and c-Src (43). Moreover, although the detailed mechanism remains unclear, TNF-α stimulation has been reported to create a feedback loop in which increased Rsk2 expression suppresses TNF signaling and CDH11 expression (44). In fact, TNF inhibitors have been shown to have high efficacy against RA in humans by suppressing TNF-α and inducing cell death in FLSs (45).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Platelet-Derived Growth Factor Receptor-Positive Cells With Anti-apoptotic Properties Accumulate in the Synovium of Patients With Rheumatoid Arthritis

et al. 2019

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Rheumatoid arthritis (RA) is an autoimmune disease caused by inflammation of the synovium and characterized by chronic polyarthritis that destroys bone and cartilage. Fibroblast-like synoviocytes (FLSs) in the synovium of patients with RA can promote cartilage and bone destruction by producing proteins such as matrix metalloproteinases and receptor activator of NF-κB ligand, thereby representing an important therapeutic target for RA. FLSs have several phenotypes depending on which cell surface proteins and adhesion factors are expressed. Identifying the cellular functions associated with different phenotypes and methods of controlling them are considered essential for developing therapeutic strategies for RA. In this study, synovial tissue was collected from patients with RA and control subjects who required surgery due to ligament injury or fracture. Immunohistological analysis was used to investigate the rates of positivity for phosphorylated platelet-derived growth factor receptor-αβ (pPDGFRαβ) and cadherin-11 (CDH11) expression, and apoptosis-related markers were assessed for each cell phenotype. Next, FLSs were isolated in vitro and stimulated with tumor necrosis factor-α (TNF-α) in addition to a combination of PDGF and transforming growth factor (2GF) to investigate pPDGFRαβ and CDH11 expression and the effects of the inhibition of TNF and cyclin-dependent kinase (CDK) 4/6 on FLSs. Immunohistological analysis showed a large percentage of pPDGFRαβ+CDH11– cells in the sub-lining layer (SL) of patients with RA. These cells exhibited increased B-cell lymphoma-2 expression, reduced TNF receptor-1 expression, resistance to cell death, and abnormal proliferation, suggesting a tendency to accumulate in the synovium. Further, in vitro 2GF stimulation of FLSs lowered, whereas 2GF + TNF stimulation increased the pPDGFRαβ/CDH11 ratio. Hypothesizing that FLSs stimulated with 2GF + TNF would accumulate in vivo in RA, we determined the therapeutic effects of TNF and CDK4/6 inhibitors. The TNF inhibitor lowered the pPDGFRαβ/CDH11 ratio, whereas the CDK4/6 inhibitor suppressed cell proliferation. However, a synergistic effect was not observed by combining both the drugs. We observed an increase in pPDGFRαβ+CDH11– cells in the SL of the RA synovium and accumulation of these cells in the synovium. We found that the TNF inhibitor suppressed FLS activity and the CDK4/6 inhibitor reduced cell proliferation.

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“…We here show for the first time that LD-RT has a positive effect on FLS, OCs, and osteoblasts which are all involved in inflammation and degenerative processes in the joints. FLS show unique features such as hyperproliferation ( 9 ) and resistance to apoptosis ( 43 ). By treating h TNF- α tg FLS with various doses of radiation we found that single doses of 0.5–2.0 Gy are able to reduce proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…FLS are considered to be the leading cells in joint destruction and strongly contribute to disease initiation, progression, and inflammation in RA ( 1 , 8 ). FLS hyperplasia in particular is a crucial factor contributing to the severity of RA via the maintenance of local inflammation alongside with cartilage destruction ( 9 ). Neutrophils on the other hand are known to be involved in the initiation and maintenance of inflammation in RA.…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism

et al. 2018

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Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.

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Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis

Cited by 18 publications

References 52 publications

Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs

Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs

Phosphorylated Platelet-Derived Growth Factor Receptor-Positive Cells With Anti-apoptotic Properties Accumulate in the Synovium of Patients With Rheumatoid Arthritis

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism

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