Osteoclasts produced from Bcl x cKO mouse bone marrow cells exhibited increased bone resorbing activity and reduced survival, in line with the results obtained within the chemical studies. We previously reported that activation of the Flupirtine pathway through the introduction of constitutively active Mek1 markedly promoted the survival of osteoclasts, and that, conversely, inhibition of the pathway by overexpressing RasDN quickly induced apoptotic cell death. The actual mechanisms by which the Erk pathways manages osteoclast survival have not been clarified yet, but we previously found that the Erk pathways negatively regulate Bim expression through the ubiquitin proteasome degradation system and that the proapoptotic Bcl 2 family protein Bim induces apoptosis of osteoclasts. Over-expression of Bcl xL while Erk activation by MekCA term, nearly completely paid for the apoptotic impact of RasDN or PD98059 only partially restored the success of Bcl x deleted osteoclasts. These results suggest that Bcl xL lies downstream of Erk in the signaling cascade and that the harmony between Bim severely and Bcl xL oversees osteoclast success. Overexpression of Bcl xL suppressed, and Bcl x knockout improved, Erk activity in osteoclasts, suggestive of negative feedback regulation of Erk activity by Bcl xL. Regardless of the habit of Bcl x cKO osteoclasts, these cells showed increased bone resorbing activity. That is in sharp contrast to the phenotype seen in Bim KO osteoclasts, which displayed reduced bone resorbing activity along with increased apoptosis. In an effort to recognize the molecular mechanisms underlying the enhanced bone resorbing function of osteoclasts, we recognized that Bcl xL managed integrin mediated d Src activation in osteoclasts through modulating ECM protein expression. Integrins are transmembrane heterodimeric glycoproteins composed of and subunits that mediate cellcell and cell matrix interactions. Ligand binding to integrins stimulates intracellular signal transduction pathways, which result in the cytoskeletal re-arrangement and de novo gene expression related to cell adhesion, spreading, and migration. The v 3 integrin, also called the vitronectin receptor, is predominantly expressed in osteoclasts. Sanjay et al. previously reported that the engagement of v 3 integrin induces the formation of a Pyk2/c Src/c Cbl complex, resulting in c Src initial and osteoclastic bone resorption, and that c Lapatinib EGFR inhibitor KO osteoclasts present decreased motility on vitronectin covered surfaces in vitro.