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

ABSTRACT:

Objectives

To 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.

Methods

Following 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??M 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).

Results

Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p?½?=?21 min). In stimulated RA-FLS cells, takinib reduced GRO?, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling.

Conclusion

Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

SUBMITTER: Scarneo SA 

PROVIDER: S-EPMC6918687 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature