It is still unclear how bispho sphonates could stimulate directly bone formation, even if many metabolic pathways have been suggested, the stimu lation of b FGF and of Bone Morphogenetic Protein 2, the upregulation of a cascade of osteo blast related genes ruxolitinib structure including BMP 2, cbfa 1, type 1 col lagen and Bone Sialo Proteins, the influence on OPG RANKL system. In addition, earlier co culture studies have shown that the presence of osteoblastic lineage cells is required also for a complete anti resorptive effect of bisphosphonates, suggesting that these drugs inhi bit osteoclast activity both directly, interfering with meva lonate pathway, but also indirectly trough osteoblast activation. All these findings strengthen the concept that osteoblastic lineage is another important target of aminobisphosphonates.
Among all these different mechanisms of osteoblast activation, it is known that COX 2 and endogenous prostaglandins regulate bone formation and osteoblast Inhibitors,Modulators,Libraries differentiation in bone marrow stem cells. On the contrary, COX 2 disruption in BMSC cultures decreased osteoblastogenesis, and general cell growth and inhibit or delay fracture healing. Since Inhibitors,Modulators,Libraries COX 2 are also involved in the early stage of bone marrow stem cell differentiation toward osteoblas tic lineage, we may suppose that bisphosphonates influence osteoblastic lineage also by promoting osteoblast differentiation and viability at least in part through COX 2 pathway. This hypothesis is in agree ment with recent data that confirm COX 2 as an impor tant target of drugs used in metabolic bone diseases, such us strontium ranelate.
On the other hand, administration of a drug that inhi bits COX 2 activity, such as non steroidal anti inflam matory drugs, Inhibitors,Modulators,Libraries seems to be associated with an inhibition of fracture healing and reduction of bone mineral density, even if it is unlikely that NSAIDs are able to block continuously all PG activity at the local level in vivo, since PGs work in an autocrine para crine manner and NSAIDs are generally given for short periods. According to these findings, our results show an increased expression of COX 2 in rat osteocytes treated with Ris and suggest that this pathway could be involved in Inhibitors,Modulators,Libraries the modulation of bone metabolism induced by aminobisphosphonates. As already mentioned, we found that Ris treatment prolongs osteocyte lifespan, reducing their apoptosis induced by GC. Considering that COX 2 expression and PGs increase have been associated Inhibitors,Modulators,Libraries with higher resistance to apoptosis and tumour promotion in tissues other than bone, the reduced kinase inhibitor Gefitinib apoptosis and the higher expression of COX 2 could be strictly linked. Moreover, Ris could have a potent influence on osteo blast precursors.