Tyrosine Kinase Inhibitor Tyrphostin AG490 Inhibits Osteoclast Differentiation in Collagenase-Induced Osteoarthritis

Abstract

The janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade plays a principal role in the signaling of a vast array of cytokines and growth factors which stimulates diverse cellular functions and immune responses. Osteoarthritis (OA) is the most common joint disease in the adult population. The present study was designed to evaluate the effects of tyrosine kinase inhibitor, tyrphostin AG490 in a mouse model of collagenase-induced osteoarthritis (CIOA). CIOA was provoked by two intraarticular (i.a.) injections of collagenase in mice and intraperitoneally (i.p.) treated with AG490 at a dose of 5 mg/kg at days 0, 5 and 10 and at a dose of 8 mg/kg at day 18. The administration of AG490 in CIOA mice inhibited osteoclast generation in bone and the loss of glycosaminoglycans and proteoglycans in cartilage. Tyrphostin decreased the levels ofIFN-y, ILl, IL-6 and IL-17 in the synovial fluid (SF) dependant on the time post AG490 administration. Limited numbers of CDllb positive Ly6G neutrophils in blood and SF along with a decrease of F4/80 positive cells in synovial fluid (SF) were observed in tyrphostin AG490-treated arthritic mice. AG490 inhibited M-CSF+RANKL-induced cytokine production by bone marrow (BM) cells and the differentiation of BM cells in vitro.

Osteoarthritis Affects Mammalian Oogenesis: Effects of Collagenase-Induced Osteoarthritis on Oocyte Cytoskeleton in a Mouse Model

“…Female outbred ICR, 8- to 10-week-old mice were used in the current investigation: 10 mice (the experimental, CIOA group) were anesthetized by sodium pentobarbital at a dose of 50 mg/kg intraperitoneally and injected by 2 IU/10 μ l collagenase (from Clostridium histolyticum , Sigma-Aldrich, Germany) into the tibiotalar intraarticular space to induce osteoarthritis (day 0). The inflammation and phases of arthritis (initial acute, developing inflammation, chronification, and established phase) were studied in earlier works, and our treated animals were used in their established phase of CIOA as previously described [ 14 , 21 ]. Nine females (the control group) were not treated by collagenase; they were anesthetized and injected i.a.…”