mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation in vitro and in vivo

Chen, Sijia; Tok, Melissa N. van; Knaup, Véronique L.; Kraal, Lianne; Pots, Desirée; Bartels, Lina; Gravallese, Ellen M.; Taurog, Joel D.; Sande, Marleen van de; Duivenvoorde, Leonie M. van; Baeten, Dominique

doi:10.3389/fimmu.2019.02344

Cited by 26 publications

(20 citation statements)

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“…Inhibition of PI3Ks was also effective in murine psoriasis ( 48 ) and collagen-induced arthritis models ( 49 ). mTOR blockade with rapamycin inhibited arthritis and affected bone remodeling in a SpA rat model and also inhibited osteogenic differentiation of SpA patients' synovial fibroblasts in vitro ( 50 ). Based on the recent data from our team and from others ( 46 – 50 ), we expect that the observed modulation of the PI3K-Akt-mTOR pathway might take place by innate-like (MAIT and γδ-T cells) and adaptive (Th17) cells or synovial fibroblasts, although this remains to be formally tested in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…mTOR blockade with rapamycin inhibited arthritis and affected bone remodeling in a SpA rat model and also inhibited osteogenic differentiation of SpA patients' synovial fibroblasts in vitro ( 50 ). Based on the recent data from our team and from others ( 46 – 50 ), we expect that the observed modulation of the PI3K-Akt-mTOR pathway might take place by innate-like (MAIT and γδ-T cells) and adaptive (Th17) cells or synovial fibroblasts, although this remains to be formally tested in future studies. The potential effects of ustekinumab on the PI3K-Akt-mTOR pathway in our study supports the concept that specific targeting of the PI3K-Akt-mTOR pathway could be beneficial in human SpA.…”

Section: Discussionmentioning

confidence: 99%

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IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

et al. 2021

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Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear.Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients.Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR).Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis.Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

et al. 2021

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“…mTOR inhibition reduced the incidence and severity of arthritis and spondylitis and blocked the associated new bone formation and erosion. Rapamycin exerted an anti-inflammatory effect on PBMC and dampened the osteogenic properties of FLS independently of IL-17A and TNFα cytokines [26].…”

Section: Fibroblast-like Synovial Cellsmentioning

confidence: 96%

“…Very recently, data on the use of the mTOR inhibitor, rapamycin, in the HLA-B27 transgenic rat model of SpA have been published [26]. mTOR inhibition reduced the incidence and severity of arthritis and spondylitis and blocked the associated new bone formation and erosion.…”

Section: Fibroblast-like Synovial Cellsmentioning

confidence: 99%

Novel immune cell phenotypes in spondyloarthritis pathogenesis

et al. 2021

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Spondyloarthritis (SpA) is a heterogeneous group of chronic inflammatory diseases of unknown etiology. Over time, the plethora of cellular elements involved in its pathogenesis has progressively enriched together with the definition of specific cytokine pathways. Recent evidence suggests the involvement of new cellular mediators of inflammation in the pathogenesis of SpA or new subgroups of known cellular mediators. The research in this sense is ongoing, and it is clear that this challenge aimed at identifying new cellular actors involved in the perpetuation of the inflammatory process in AxSpA is not a mere academic exercise but rather aims to define a clear cellular hierarchy. Such a definition could pave the way for new targeted therapies, which could interfere with the inflammatory process and specific pathways that trigger immune system dysregulation and stromal cell activity, ultimately leading to significant control of the inflammation and new bone formation in a significant number of patients. In this review, we will describe the recent advances in terms of new cellular actors involved in the pathogenesis of SpA, focusing our attention on stromal cells and innate and adaptive immunity cells.

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“…While animal models provide an ideal basis for in-depth molecular analysis of target tissues in SpA to elucidate causal relationships between the upregulation of specific immune pathways and development of key SpA features, complimentary studies performing serial advanced molecular imaging or biosample collection in individuals with an increased risk of developing SpA or PsA, or in patients who have been recently diagnosed withSpA, are essentially required if we want to translate findings in animal models of SpA to human disease. The goal of studying the preclinical stage of the disease would be to find better diagnostic markers to allow an earlier diagnosis and open up opportunities for preventive treatment strategies (108)(109)(110). If IL-23 dysregulation in the pre-clinical phase of disease, as observed in various animal models, can be confirmed in human pre-clinical SpA, it could be speculated that IL-23 targeting may be effective in preventing disease, in contrast to the lack of effect observed with IL-23 blocking in established SpA.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models

2021

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Spondyloarthritis (SpA) is a spectrum of chronic inflammatory joint diseases that frequently presents with inflammation of the axial skeleton, peripheral joints, entheses, skin, and gut. Understanding SpA pathogenesis has been proven challenging due to the limited availability of human target tissues. In recent years, the interleukin (IL)-23/IL-17 pathway has been implicated in the pathogenesis of SpA, in addition to the Tumor Necrosis Factor Alpha (TNF-α) cytokine. The underlying molecular mechanisms by which the IL-23/IL-17 pathway triggers disease initiation, both in the joints as well as at extra-musculoskeletal sites, are not precisely known. Animal models that resemble pathological features of human SpA have provided possibilities for in-depth molecular analyses of target tissues during various phases of the disease, including the pre-clinical initiation phase of the disease before arthritis and spondylitis are clinically present. Herein, we summarize recent insights gained in SpA animal models on the role of the IL-23/IL-17 pathway in immune activation across affected sites in SpA, which include the joint, entheses, gut and skin. We discuss how local activation of the IL-23/IL-17 axis may contribute to the development of tissue inflammation and the onset of clinically manifest SpA. The overall aim is to provide the reader with an overview of how the IL-23/IL-17 axis could contribute to the onset of SpA pathogenesis. We discuss how insights from animal studies into the initiation phase of disease could instruct validation studies in at-risk individuals and thereby provide a perspective for potential future preventive treatment.

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mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation in vitro and in vivo

Cited by 26 publications

References 64 publications

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

Novel immune cell phenotypes in spondyloarthritis pathogenesis

The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models

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