steoclast Formation expression in M-CSF-primed OCPs; and 2) over-expression of RelB significantly inhibits RANKL-induced OC formation and NFATc1 mRNA expression. These are consistent with the reports that RelB acts as a transcriptional repressor of inflammatory mediators by forming an inactive complex with RelA. TNF SAR 405 web induction of RelB to inhibit NFATc1 activation could explain why TNF alone can significantly increase OCPs numbers through M2 to M1 switching, while having very limited ability to induce terminal OCP differentiation into OCs. In contrast, RANKL strikingly increases OC formation from TNF-primed OCPs compared to OCPs induced by M-CSF alone since it can efficiently degrade RelB protein, resulting in sustained activation of NFATc1 to promote OC formation. Although over-expression of RelB can significantly enhance TNF-induced OC formation, this effect is still lower than that of RANKL since it peaks one day later than that of RANKL. Thus, the ability of TNF alone to induce terminal OC differentiation in physiological and pathologic conditions is limited. In summary, our findings provide further evidence of positive and negative effects of TNF on OC formation through its induction of RelB. TNF induction of RelB in OCPs limits OC differentiation in the absence of other stimulators and it also directly limits RANKL-induced OC formation by inhibiting NFATc1 activation. However, TNF-induced RelB also directly mediates terminal OC differentiation independently of NFATc1. Our findings show that 
the dominant role of TNF is to expand the pool of OCPs with enhanced OC forming potential by switching the differentiation of M-CSF-induced M2 resident to M1 inflammatory macrophages. Thus, strategies to degrade RelB could reverse the differentiation of TNF-induced M1 to M2 macrophages and would represent a novel therapeutic approach for inflammatory arthritides. Type 2 diabetes is one of the major causes of atherosclerosis and an independent risk factor of cardiovascular events. Indeed, it has been reported that the prevalence of coronary and peripheral artery disease is 2- to 4-fold higher, and stroke risk was also 2-fold higher in overt type 2 diabetic patients. To prevent these atherosclerotic events, it is important to detect and intervene early in the development of atherosclerosis. Recently, endothelial cell dysfunction has been shown to precede endothelial thickening and atheroma development, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1972888 and has been reported to be an important predictor of cardiovascular events also in type 2 diabetic patients. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19728767 Moreover, they are used for therapeutic surrogate parameters of the early phase of atherosclerosis because of their plasticity. Flow-mediated dilation of the brachial artery reflects endothelial nitric oxide bioavailability and is widely used as a marker for early atherosclerosis. Impaired FMD is associated with type 2 diabetes independent of glucose levels and may, in part, explain the increased cardiovascular risk in this patient population. Therefore it is important that diabetic therapies achieve glycemic control and maintain/improve FMD to prevent the development of vascular complications. GLP-1 mimetics are a recently approved treatment strategy for improving glycemic control and lowering hemoglobin A1c in type 2 diabetics. However, various additional health benefits beyond glucose control are also expected with GLP-1 therapy including protection from macro-vascular complications. For example, administration of GLP-1 improved endotheli
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