Tyrosine kinase inhibitor tyrphostin AG490 retards chronic joint inflammation in mice.
Tyrphostin AG490 is a Janus kinase (JAK) 2 inhibitor that is clinically used as an anticancer agent and is also effective in various models of inflammatory and autoimmune diseases. In this study, we examined the effects of tyrphostin AG490 on the development of collagenase-induced osteoarthritis (CIOA). Our results showed that tyrphostin-ameliorated cartilage and bone destructions. This effect was associated with decreased expression of signal transducers and activators of transcription 3 (STAT3), phosphorylated JAK2, Dickkopf homolog 1, and receptor activator of nuclear factor κB ligand (RANKL) in the joints of arthritic mice. Tyrphostin AG490 suppressed STAT3 phosphorylation and the expression of tumor necrosis factor-related apoptosis-inducing ligand and RANKL by synovial fluid cells. The drug inhibited RANKL-induced osteoclast differentiation in vitro. Molecules, such as tyrphostin AG490 that limit bone erosion and influence osteoclast generation, might have therapeutic utility in joint degenerative disorders.
Department of Immunology, Institute of Microbiology, 1113, Sofia, Bulgaria.
Valeriya
V
Gyurkovska
Tsvetanka
T
Stefanova
Petya
P
Dimitrova
Svetla
S
Danova
Rositsa
R
Tropcheva
Nina
N
Ivanovska
D000818:Animals; D000831:Animals, Newborn; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053614:Janus Kinase 2 / Q000378:metabolism; D007596:Joints / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D053245:RANK Ligand / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D016207:Cytokines; C501127:Dkk1 protein, mouse; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D015850:Interleukin-6; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505689:Tnfsf11 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C577686:interleukin-6, mouse; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2