No abstract

Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis-caused bone destruction, results from an increase of bone-resorbing osteoclasts (OCs) induced by inflammation. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated that the effect of urokinase-type plasminogen activator (uPA) on inflammatory osteoclastogenesis induced by lipopolysaccharide (LPS), which is a potent stimulator of bone resorption in inflammatory diseases. We found that the uPA deficiency promoted inflammatory osteoclastogenesis and bone loss induced by LPS. We also showed that LPS induced the expression of uPA, and the uPA treatment attenuated the LPS-induced inflammatory osteoclastogenesis of RAW264.7 mouse monocyte/macrophage lineage cells. Additionally, we showed that the uPA-attenuated inflammatory osteoclastgenesis is associated with the activation of plasmin/protease-activated receptor (PAR)-1 axis by uPA. Moreover, we examined the mechanism underlying the effect of uPA on inflammatory osteoclastogenesis, and found that uPA/plasmin/PAR-1 activated the adenosine monophosphate-activated protein kinase (AMPK) pathway through Ca2+/calmodulin dependent protein kinase kinase (CaMKK) activation, and attenuated inflammatory osteoclastogenesis by inactivation of NF-κB in RAW264.7 cells. These data suggest that uPA attenuated inflammatory osteoclastogenesis through the plasmin/PAR-1/Ca2+/CaMKK/AMPK axis. Our findings may provide a novel therapeutic approach to bone loss caused by inflammatory diseases.

The low-temperature {1. 3 -20.0 K) high-magnetic-field (0 -10 T) heat capacity and the magnetization and magnetic susceptibility (1.7 -300 K) of the strongly Pauli paramagnetic RCo2 (R =Sc, Y, or Lu) compounds with the MgCu2-type structure were measured. The heat-capacity results for ScCo2, YCo~, and LuCo2 show that the electronic specific-heat constant decreases with increasing magnetic fields (by 7%, 4%%uo, and 10', respectively, at 10 T). For YCo2 the coefficient of the T term (P) in the heat capacity is found to increase by 18% at 10 T, but for ScCo2 and LuCo2 P remains constant within experimental error. Analyses based on several theoretical models of the quenching of spin fluctuations by high magnetic fields suggest that the characteristic spinfluctuation temperature is -20 K for ScCo2, -35 K for YCo2, and -16 K for LuCo2. The magnetization and the field dependence of the magnetic susceptibility of the same samples as used in the heat-capacity measurements indicate the presence of ferromagnetic impurities in the samples, but the estimated concentrations are sufficiently low that they probably have no effect on the observed heat capacities. Maxwell's thermodynamics relationship between the field dependence of the heat capacity and the temperature dependence of the magnetic susceptibility has been examined.

Renal fibrosis is the final common pathway of a wide variety of chronic kidney diseases. Myofibroblast formation via the differentiation of from tissue-resident fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs), and epithelial-to-mesenchymal transition (EMT) is known to play a pivotal role in the development of renal fibrosis. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of alpha 2-antiplasmin (α2AP) in myofibroblast formation and the development of renal fibrosis. We observed the development of renal fibrosis using unilateral ureteral obstruction (UUO). α2AP had accumulated in the UUO-induced obstructed kidneys and α2AP deficiency attenuated UUO-induced renal fibrosis in mice. The degree of myofibroblast formation in the obstructed kidneys of α2AP−/− mice was less than that in α2AP+/+ mice. In vitro, α2AP induced myofibroblast formation in renal tubular epithelial cells (RTECs), renal fibrosblasts, and bone marrow-derived mesenchymal stem cells (MSCs). α2AP also induced the production of TGF-β, which is known to be a key regulator of myofibroblast formation and fibrosis. α2AP-induced the TGF-β production was significantly reduced by SP600125, c-Jun N-terminal kinase (JNK) specific inhibitor. Our findings suggest that α2AP induces myofibroblast formation in the obstructed kidneys, and mediates the development of renal fibrosis.