Nivocasan

Osteoporosis is a degenerative metabolic disease caused by an imbalance between osteogenesis and osteoclastogenesis. Increased levels of proinflammatory cytokines combined with decreased estrogen levels, which are commonly seen in postmenopausal women, can lead to overactivation of osteoclasts. Therefore, targeting osteoclast maturation may represent a novel strategy for both treating and preventing osteoporosis. Auranofin is a gold-based compound first approved in 1985 for the treatment of rheumatic diseases. Here, we examined whether auranofin suppresses osteoclast differentiationin vitroandin vivo. Auranofin was shown to suppress receptor activator of NF-κB ligand- (RANKL-) induced osteoclastogenesis in mouse bone marrow macrophages (BMMs) and Raw264.7 macrophages. Cotreatment of macrophages with auranofin blocked the RANKL-induced inhibitors ofκB kinase (IKK) phosphorylation, resulting in inhibition of nuclear translocation of p65. The pan-caspase inhibitor nivocasan potently reduced not only inflammasome-mediated interleukin-1β(IL-1β) secretion but also osteoclast differentiation in BMMs. Auranofin suppressed inflammasome activation, as evidenced by decreased production of cleaved IL-1βin both bone marrow-derived macrophages (BMDMs) and J774.A1 cells. Loss of both bone mass in ovariectomized mice was significantly recovered by oral administration of auranofin. Taken together, these data strongly support the use of auranofin for the prevention of osteoclast-related osteoporosis.

Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.