Lack of Bim selleck inhibitor leads to enhanced osteoclast survival and the pro survival factor M CSF decreases Bim levels in osteoclasts and osteoclast precursors, probably by increasing ubiquitin Inhibitors,Modulators,Libraries dependent degradation of Bim via upreg ulation of Inhibitors,Modulators,Libraries cCbl. The role of Bim in BP induced osteoclast apoptosis is not known, although a recent study showed that apoptosis of MCF 7 breast cancer cells induced by the BP risedronate involved increased levels of Bim. Upregula tion of Mcl 1 by RANKL is therefore a likely mechanism by which RANKL prevents BP induced apoptosis of osteoclasts. Conclusions We have shown that RANKL protects osteoclasts from the pro apoptotic and hence anti resorptive effects of the BPs CLO and ALN in vitro. This protective effect of RANKL is likely to be mediated at least in part by an increase in the level of the anti apoptotic protein Mcl 1.

The ability of RANKL, together with Inhibitors,Modulators,Libraries other factors such as TNF, to rescue osteoclasts from the pro apoptotic effects of BPs may account for the apparent lack of effectiveness of BPs in preventing local, inflam mation induced bone loss in RA. The salivary gland system, comprised of the parotid, sub mandibular, sublingual, and minor salivary glands, secretes flu ids rich in proteins that are critical for the maintenance of oral health. Saliva functions to buffer the acidification produced by bacteria residing within the oral cavity, replace ions, moisten food, and lubricate the oral cavity and esophagus. Saliva also contains diges tive enzymes like amylase, anti microbial substances like secretory immunoglobulins, histatins, and splunc, and growth factors like epidermal growth factor.

While there are multiple underlying causes for decreased secretions of saliva, one Inhibitors,Modulators,Libraries of the more severe causes of xerostomia sicca, or dry mouth disease, results from an autoimmune disease, referred to as Sj?grens syndrome, in which the immune system targets initially the salivary and or lacrimal glands. Despite expanding efforts to define the genetic, environmen tal, and immunological bases of SjS, the underlying etiology of this disease remains ill defined. Over the past 20 years, a vari ety of mouse strains have been developed to study the immuno pathophysiological nature of SjS. Based on results of studies using non obese diabetic mice and various sin gle gene knockout congenic partner strains of NOD, we have postulated that the development Inhibitors,Modulators,Libraries and onset of autoimmune exocrinopathy can be divided into at least three distinct tem poral, yet consecutive and overlapping, phases.

In phase 1, aberrant genetic, physiological, and biochemical activities, resulting presumably from retarded salivary gland develop ment and increased acinar cell apoptosis, occur between 6 and 10 weeks of age. In phase 2, occurring around 10 to 18 weeks of age, exocrine gland injury is observed in conjunction with the appearance of leukocytic infiltrates and formation of lymphocytic foci twice consisting mostly of T and B cell aggregates.