casein-kinase-ii and Arthritis--Rheumatoid

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

Topics: Animals; Arthritis, Rheumatoid; Casein Kinase II; Cell Proliferation; Cells, Cultured; Fibroblasts; Interleukin-6; Matrix Metalloproteinase 3; Mice; Patient Acuity; Proteomics; Synovial Membrane; Synoviocytes; Tumor Suppressor Protein p53

The Huayu-Qiangshen-Tongbi (HQT) decoction, a Chinese medical formula, has been identified to show a potent therapeutic effect on rheumatoid arthritis (RA). However, the specific molecular mechanism of HQT in RA has not been well studied. In the present study, LPS-treated human rheumatoid fibroblast-like synoviocyte (FLS) MH7A cells and collagen-induced arthritis (CIA) mice were utilized as

Topics: Animals; Arthritis, Rheumatoid; Casein Kinase II; China; Fibroblasts; Humans; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; MicroRNAs; NF-kappa B; Synoviocytes; Tumor Necrosis Factor-alpha

Studies have demonstrated that CK2 is engaged in CD4. Peripheral blood and synovial fluid mononuclear cells (PBMC and SFMC) of RA patients, as well as splenocytes of collagen-induced arthritis (CIA) mice were treated with different doses of CK2 inhibitor CX4945. The expression of CK2 was upregulated in CD4. CK2 serves as an important regulator of the Th1 and Th17 cell axes in RA, thus contributing to the disease aggravation.

Topics: Animals; Arthritis, Rheumatoid; Casein Kinase II; Humans; Leukocytes, Mononuclear; Mice; Naphthyridines; Phenazines; Protein Kinase Inhibitors; Th1 Cells; Th17 Cells

By means of heparin-affinity and glycyrrhizin (GL)-affinity column chromatographies (HPLC), a GL-binding phospholipase A2 (gbPLA2) was selectively purified from the synovial fluids of patients with rheumatoid arthritis. This purified gbPLA2 was identified as a secretory type IIA PLA2 (sPLA2-IIA) since it was crossreacted with anti-sPLA2-IIA serum. The activity of purified sPLA2-IIA was inhibited by glycyrrhetinic acid (GA) and a GA derivative (oGA) in a dose-dependent manner, but it was more sensitive to GA than GL. Furthermore, it was found that (i) purified sPLA2-IIA is phosphorylated by casein kinase II (CK-II) in vitro; (ii) this phosphorylation induces in a significant stimulation of PLA2 activity; and (iii) oGA at one-tenth the concentration of GL inhibits the CK-II-mediated stimulation of sPLA2-IIA activity. These results show that (i) sPLA2-IIA is a GL-binding protein; and (ii) CK-II mediates stimulation of its PLA2 activity in vitro.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Casein Kinase II; Chromatography, Liquid; Crotalid Venoms; Enzyme Inhibitors; Glycyrrhetinic Acid; Glycyrrhizic Acid; Group II Phospholipases A2; Humans; In Vitro Techniques; Phospholipases A; Phospholipases A2; Phosphorylation; Protein Binding; Protein Serine-Threonine Kinases; Stimulation, Chemical; Synovial Fluid