Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular matrix turnover in bovine articular cartilage ex vivo

Kjelgaard-Petersen, Cecilie Freja; Sharma, Neha; Kayed, Ashref; Karsdal, Morten A.; Mobasheri, Ali; Hägglund, Per; Bay‐Jensen, Anne‐Christine; Thudium, Christian S.

doi:10.1016/j.bcp.2018.07.034

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…This indicates that baricitinib treatment, in the timespan of the current study, provided limited modulation of cartilage turnover. C2M is a type II collagen fragment released from hyaline cartilage upon proteolytic cleavage by MMPs [ 27 ]. C2M is increased in patients with RA compared to healthy controls [ 24 ] and can be modulated by anti-inflammatory treatment [ 17 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

et al. 2020

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Background Tissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib in patients with active rheumatoid arthritis (RA). Methods Serum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX-I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2-mg or 4-mg baricitinib (RA-BUILD, NCT01721057). Mixed-model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis. Results Treatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4-mg significantly reduced C1M from baseline by 21% compared to placebo (p < 0.01); suppression was sustained at week 12 (27%, p < 0.001). Baricitinib 4-mg reduced C3M and C4M at week 4 by 14% and 12% compared to placebo, respectively (p < 0.001); they remained reduced by 16% and 11% at week 12 (p < 0.001). In a pooled analysis including all treatment arms, patients with the largest reduction (upper 25% quartile) in C1M, C3M, and C4M by week 12 had significantly greater clinical improvement in the Simplified Disease Activity Index at week 12 compared to patients with the smallest reduction (lowest 25% quartile). Conclusion Baricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement. Trial registration ClinicalTrials.gov NCT01721057; date of registration: November 1, 2012

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Section: Discussionmentioning

confidence: 99%

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

et al. 2020

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“…Blocking OSM in a collagen-induced arthritis mouse model improves joint inflammation and cartilage damage (26). Furthermore, recent studies have demonstrated that inhibition of OSM-induced RAFLS pro-inflammatory mechanisms and cartilage degradation are rescued in the presence of JAK-STAT inhibitors (27, 28), effects that are, in part, mediated by a switch in the metabolic profile of the cell (29). Conversely, OSM is a pleiotropic cytokine often displaying divergent effects with both pro- and anti-inflammatory effects depending on the cell type and microenvironment.…”

Section: Introductionmentioning

confidence: 99%

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

et al. 2019

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Objectives: Oncostatin M (OSM), a pleiotropic cytokine and a member of the gp130/IL-6 cytokine family, has been implicated in the pathogenesis of autoimmune diseases. Here we investigate the mechanisms by which its synergistic interactions with TNFα regulate the cellular bioenergetics and invasive function of synovial cells from patients with Rheumatoid Arthritis. Methods: Primary RA synovial fibroblasts (RAFLS) and human umbilical vein endothelial cells (HUVEC) were cultured with OSM alone or in combination with TNFα. Pro-inflammatory cytokines, angiogenic growth factors and adhesion molecules were quantified by real-time PCR and ELISA. Invasion, angiogenesis and cellular adhesion were quantified by Transwell invasion chambers, Matrigel tube formation assays, and adhesion binding assays. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyser. Key metabolic genes (GLUT-1, HK2, PFKFB3, HIF1α, LDHA, PKM2) and transcription factor STAT3 were measured using real-time PCR and western blot. Results: OSM differentially regulates pro-inflammatory mediators in RAFLS and HUVEC, with IL-6, MCP-1, ICAM-1, and VEGF all significantly induced, in contrast to the observed inhibition of IL-8 and GROα, with opposing effects observed for VCAM-1 depending on cell type. Functionally, OSM significantly induced angiogenic network formation, adhesion, and invasive mechanisms. This was accompanied by a change in the cellular bioenergetic profile of the cells, where OSM significantly increased the ECAR/OCR ratio in favor of glycolysis, paralleled by induction of the glucose transporter GLUT-1 and key glycolytic enzymes (HK2, PFKFB3, HIF1α). OSM synergizes with TNFα to differentially regulate pro-inflammatory mechanisms in RAFLS and HUVEC. Interestingly, OSM differentially synergizes with TNFα to regulate metabolic reprogramming, where induction of glycolytic activity with concomitant attenuation of mitochondrial respiration and ATP activity was demonstrated in RAFLS but not in HUVEC. Finally, we identified a mechanism, whereby the combination of OSM with TNFα induces transcriptional activity of STAT3 only in RAFLS, with no effect observed in HUVEC. Conclusion: STAT3 mediates the differential effects of OSM and TNFα on RAFLS and EC function. Targeting OSM or downstream signaling pathways may lead to new potential therapeutic or adjuvant strategies, particularly for those patients who have sub-optimal responses to TNFi.

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“…As an anti-inflammatory compound, TPCA-1 interferes with the activation of NF-κB by inhibiting IKK-2 (15,40). In the previous work, HA-AuNCs/T/P were internalized by inflammatory cells and inhibited the production of inflammatory factors such as IL-6, TNF-α, and reactive oxygen species (ROS) in a prophylactic treatment (15).…”

Section: Discussionmentioning

confidence: 99%

Targeted and Combined TPCA-1-Gold Nanocage Therapy for In Vivo Treatment of Inflammatory Arthritis

Wang

Yang

et al. 2020

AAPS PharmSciTech

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Rheumatoid arthritis (RA) is an autoimmune disease that is currently incurable. Inhibition of inflammation can prevent the deterioration of RA. 2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) suppresses inflammation via the inhibition of nuclear factor-κ (NF-κB) signaling pathway. Gold-based therapies have been used to treat inflammatory arthritis since the 1940s. Hyaluronic acid (HA) is a targeting ligand for CD44 receptors overexpressed on activated macrophages. Therefore, a combined therapy based on TPCA-1, gold, and HA was explored for the treatment of RA in this study. We used gold nanocages (AuNCs) to load TPCA-1 and modified the TPCA-1 (T) loaded AuNCs with HA and peptides (P) to construct an anti-inflammatory nanoparticle (HA-AuNCs/T/P). An adjuvant-induced arthritis (AIA) mice model was used to investigate the in vivo anti-inflammatory efficacy of HA-AuNCs/T/P. In vivo distribution results showed that HA-AuNCs/T/P had increased and prolonged accumulation at the inflamed paws of AIA mice. Treatment by the HA-AuNCs/T/P suppressed joint swelling and alleviated cartilage and bone damage. By loading to HA-AuNCs/T/P, the effective concentration of TPCA-1 was greatly reduced from 20 to 0.016 mg/kg mice. This study demonstrated that HA-AuNCs/T/P could effectively suppress inflammation and alleviate the symptoms of AIA mice, suggesting a great potential of HA-AuNCs/T/P for the treatment of RA.

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Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular matrix turnover in bovine articular cartilage ex vivo

Cited by 16 publications

References 46 publications

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

STAT3 Mediates the Differential Effects of Oncostatin M and TNFα on RA Synovial Fibroblast and Endothelial Cell Function

Targeted and Combined TPCA-1-Gold Nanocage Therapy for In Vivo Treatment of Inflammatory Arthritis

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