Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice

Abstract

ObjectivesTo examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells.MethodsFollowing the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF).ResultsHere, we show takinib’s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling.ConclusionOur findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

Host Response to Biomaterials for Cartilage Tissue Engineering: Key to Remodeling

“…CIA is the most extensively studied model of rheumatoid arthritis (RA), mainly involving distal joints (especially the posterior ankle joint) (Wu et al, 2015). Its pathological features are similar to those of RA, including synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction (Scarneo et al, 2019;De et al, 2020). Col II is the major protein in the cartilage of joints targeted by RA, and anti-Col II autoantibodies are present in the serum of RA patients, which indicates that Col II can induce an autoimmune response of an arthritic nature in the body (Manivel et al, 2015).…”

Ultra-purification of Lipopolysaccharides reveals species-specific signalling bias of TLR4: importance in macrophage function

“…In order to further elucidate whether TLR4 signalling was individually-biased to bacterial LPS in this scenario, we utilised pharmacological interventions to alter TLR-specific intracellular signalling proteins mitogen-activated protein kinase kinase kinase 7 (MAPK7 also known as TAK1) and TANK-binding kinase 1 (TBK1). TAKANIB and MRT67307 have been well documented to prevent activation of these kinases in a highly-selective and controlled manner, thus we sought to use these agents to distinguish the activation pathways of TLR4, and ultimate phosphorylation of p65 or IRF3, respectively 21 , 22 .…”

Repository corticotropin injection attenuates collagen-induced arthritic joint structural damage and has enhanced effects in combination with etanercept

“…Bone resorption, ankle inflammation, and ankle cartilage damage were scored as previously described [ 27 , 31 ] with the addition of 0.5, reflecting very minimal resorption affecting only marginal zones and only a few joints, minimal focal inflammation, and very minimal decrease in toluidine blue staining affecting only marginal zones, respectively. Ankle pannus was scored as previously described [ 32 ], and ankle periosteal new bone formation (measured at 16× magnification) was scored according to the following criteria: 0 = normal (no periosteal proliferation); 0.5 = minimal focal or multifocal proliferation (width measures < 127 μm [1–2 U] at any location); 1 = minimal multifocal proliferation (width at any location measures 127–252 μm [3–4 U]; 2 = mild multifocal proliferation on tarsals, diffuse in some locations, width at any location 253–441 μm [5–7 U]; 3 = moderate multifocal proliferation on tarsals, diffuse in most other locations, width at any location measures 442–630 μm [8–10 U]; 4 = marked multifocal proliferation on tarsals, diffuse at most other locations, width at any location measures 631–819 μm [11–13 U]; and 5 = severe, multifocal proliferation on tarsals, diffuse at most other locations, width at any location measures > 819 μm [> 13 U] [ 25 , 33 ].…”

“…tarsals, diffuse at most other locations, width at any location measures 631-819 μm[11-13 U]; and 5 = severe, multifocal proliferation on tarsals, diffuse at most other locations, width at any location measures > 819 μm [> 13 U][25,33].Anti−collagen type II antibody enzyme-linked immunosorbent assay Serum was collected at necropsy and frozen at −80 o C until analysis. Rat anti-collagen type II (CII) immunoglobulin G (IgG) was quantified using an enzyme-linked immunosorbent assay (ELISA) kit (Chondrex, Inc., Redmond, WA) following the manufacturer's instructions.…”