Anti-STAB2 (aa 1203-1334) polyclonal antibody

Backgroundvon Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. ObjectivesTo investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. Patients/MethodsIn 364 type1 VWD and 240 type2 VWD patients from the nationwide cross-sectional Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. ResultsIn type1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0IUdL(-1) per allele; 95% confidence interval [CI]-6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3IUdL(-1) per allele; 95%CI-7.9 to -0.6) and lower VWF:Act (-5.7 IUdL(-1) per allele; 95%CI-10.9 to -0.5). In type2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. ConclusionsGenetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type1 VWD, but not in type2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.

Fusion and apoptosis share a breakdown of the membrane phospholipids asymmetry, modes of which are largely unknown in osteoclastogenesis. Here, we investigated the externalization of phosphatidylserine (PS) and its receptors, and their biological functions in osteoclastogenesis. Strong immunoreactivities in vivo for the PS receptors TIM4, BAI1, and STAB2 were observed in the TRAP-positive multinucleated cells in the alveolar bone that was being remodeled around the developing dental follicles in rats. These receptors were significantly upregulated during M-CSF/RANKL-induced in vitro osteoclastogenesis using mouse bone marrow-derived cells. PS externalization in preosteoclasts was increased by the M-CSF/RANKL treatment. Multinucleation of preosteoclasts was markedly inhibited by antibodies against PS and its receptors. Among the investigated lipid transporter proteins, floppases (Abcb4,Abcc5, andAbcg1) were upregulated, whereas flippases (Atp11candAtp8a1) downregulated during osteoclastogenesis. Preosteoclast fusion was markedly blocked by the ATPase inhibitor Na(3)VO(4)and siRNAs againstAbcc5andAbcg1, revealing the importance of these lipid transporters in PS externalization. Further, the levels ofCd47andCd31, don't-eat-me signal inducers, were increased or sustained in the early phase of osteoclastogenesis, whereas those ofAnnexinIandMfg-e8, eat-me signals inducers, were increased in the late apoptotic phase. In addition, Z-VAD-FMK, a pan caspase inhibitor, had no effect on preosteoclast fusion in the early phase of osteoclastogenesis, whereas Abs against PS, TIM4, and BAI1 decreased osteoclast apoptosis during the late phase. These results suggest that PS externalization is essential for the whole process of osteoclastogenesis and share PS receptors and transporters in the early stage fusion and late stage apoptosis. Therefore, modulation of PS and its receptors could be a useful strategy to develop anti-bone resorptive agents.