Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6

Ruscitti, Piero; Liakouli, Vasiliki; Panzera, Noemi; Angelucci, Adriano; Berardicurti, Onorina; Nino, Elena Di; Navarini, Luca; Vomero, Marta; Ursini, Francesco; Mauro, Daniele; Dolo, Vincenza; Ciccia, Francesco; Giacomelli, Roberto; Cipriani, Paola

doi:10.3390/ph15050622

Cited by 11 publications

(7 citation statements)

References 32 publications

(66 reference statements)

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“…Western blotting was conducted as previously described [ 22 ]. The total proteins of synovial tissue and cells were extracted and quantified with a BCA protein concentration kit (Beyotime, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

AXL Inhibits Proinflammatory Factors to Relieve Rheumatoid Arthritis Pain by Regulating the TLR4/NF-κB Signaling Pathway

Zhou

2022

Evidence-Based Complementary and Alternative Medicine

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Objective. This study aims to explore the role and mechanism of AXL receptor tyrosine kinase (AXL) in relieving inflammatory pain caused by rheumatoid arthritis (RA). Methods. RA mouse model was constructed by collagen antibody induction. RT-qPCR and Western blot were used to detect the level of AXL in RA fibroblast-like synovial cells (RA-FLS) and joint synovium. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) were detected by ELISA. The inflammatory infiltration in joints was determined via HE staining. The mechanical abnormal pain and hyperalgesia were detected by the Von Frey microfilament test. The protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (3COX-2), toll-like receptor 4 (TLR4), p65, and phosphor (p)-p65 were detected by Western blotting. Results. The expression of AXL in RA-FLS and RA mice was downregulated, while the expression of iNOS and COX-2 was upregulated. The levels of inflammatory cytokines IL-6, TNF-α, and NO were increased in RA-FLS and RA mice. RA mice presented inflammatory cell infiltration, bone and cartilage destruction, and joint space stenosis. AXL overexpression alleviated inflammatory cell infiltration, inflammatory cytokine secretion, and pathological injury in RA mice. Additionally, AXL overexpression inhibited the expression of TLR4 and p-p65. Conclusion. AXL inhibits inflammatory pain in RA mice by suppressing TLR4/NF-κB pathway.

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Section: Methodsmentioning

confidence: 99%

AXL Inhibits Proinflammatory Factors to Relieve Rheumatoid Arthritis Pain by Regulating the TLR4/NF-κB Signaling Pathway

Zhou

2022

Evidence-Based Complementary and Alternative Medicine

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“…In addition, translational findings suggested that the administration of tofacitinib could improve some pathogenic mechanisms associated with accelerated atherosclerosis [ 28 – 30 ]. In fact, the inhibitory effects of tofacitinib have been recently shown on myofibroblast differentiation by transforming growth factor β and IL-6 [ 29 ]. Both in vitro and in vivo findings showed that tofacitinib may have anti-angiogenic properties [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

The effects of suppressing inflammation by tofacitinib may simultaneously improve glycaemic parameters and inflammatory markers in rheumatoid arthritis patients with comorbid type 2 diabetes: a proof-of-concept, open, prospective, clinical study

Di Muzio,

Di Cola,

Shariat Panahi

et al. 2024

Arthritis Res Ther

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Background A consistent connection has been increasingly reported between rheumatoid arthritis (RA), insulin resistance (IR), and type 2 diabetes (T2D). The β-cell apoptosis induced by pro-inflammatory cytokines, which could be exaggerated in the context of RA, is associated with increased expression pro-apoptotic proteins, which is dependent on JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) activation. On these bases, we aimed to evaluate if the administration of tofacitinib, a potent and selective JAK inhibitor, could simultaneously improve glycaemic parameters and inflammatory markers in patients with RA and comorbid T2D. Methods The primary endpoint was the change in the 1998-updated homeostatic model assessment of IR (HOMA2-IR) after 6 months of treatment with tofacitinib in RA patients with T2D. Consecutive RA patients with T2D diagnosis were included in this proof-of-concept, open, prospective, clinical study, which was planned before the recent emergence of safety signals about tofacitinib. Additional endpoints were also assessed regarding RA disease activity and metabolic parameters. Results Forty consecutive RA patients with T2D were included (female sex 68.9%, mean age of 63.4 ± 9.9 years). During 6-month follow-up, a progressive reduction of HOMA2-IR was observed in RA patients with T2D treated with tofacitinib. Specifically, a significant effect of tofacitinib was shown on the overall reduction of HOMA2-IR (β = − 1.1, p = 0.019, 95%CI − 1.5 to − 0.76). Also, HOMA2-β enhanced in these patients highlighting an improvement of insulin sensitivity. Furthermore, although a longer follow-up is required, a trend in glycated haemoglobin reduction was also recorded. The administration of tofacitinib induced an improvement in RA disease activity, and a significant reduction of DAS28-CRP and SDAI was observed; 76.8% of patients achieved a good clinical response. In this study, no major adverse events (AEs) were retrieved without the identification of new safety signals. Specifically, no life-threatening AEs and cardiovascular and/or thromboembolic events were recorded. Conclusions The administration of tofacitinib in RA with T2D led to a simultaneous improvement of IR and inflammatory disease activity, inducing a “bidirectional” benefit in these patients. However, further specific designed and powered studies are warranted to entirely evaluate the metabolic effects of tofacitinib in RA patients with T2D.

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“…and alpha actin-2 ( Acta2 ), and their expression was decreased by dissociation of mitochondrial HK2. A myofibroblast signature was described in RA FLS from a high-inflammation synovium ( 63 , 64 ). Other genes like periostin were already associated with migration and invasion of synoviocytes ( 65 ).…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes

et al. 2023

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BackgroundGlucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype.MethodsHK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)–HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice.ResultsCobalt chloride (CoCl2) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN.ConclusionOur results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.

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Tofacitinib May Inhibit Myofibroblast Differentiation from Rheumatoid-Fibroblast-like Synoviocytes Induced by TGF-β and IL-6

Cited by 11 publications

References 32 publications

AXL Inhibits Proinflammatory Factors to Relieve Rheumatoid Arthritis Pain by Regulating the TLR4/NF-κB Signaling Pathway

AXL Inhibits Proinflammatory Factors to Relieve Rheumatoid Arthritis Pain by Regulating the TLR4/NF-κB Signaling Pathway

The effects of suppressing inflammation by tofacitinib may simultaneously improve glycaemic parameters and inflammatory markers in rheumatoid arthritis patients with comorbid type 2 diabetes: a proof-of-concept, open, prospective, clinical study

Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes

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