Sclerostin and DKK1 Inhibition Preserves and Augments Alveolar Bone Volume and Architecture in Rats with Alveolar Bone Loss.

Alveolar bone is a mechanosensitive tissue that provides structural support for teeth. Alveolar bone loss is common with aging, menopause, tooth loss, and periodontitis and can lead to additional tooth loss, reduced denture fixation, and challenges in placing dental implants. The current studies suggest that sclerostin and DKK1, which are established osteocyte-derived inhibitors of bone formation, contribute to alveolar bone loss associated with estrogen ablation and edentulism in rats. Estrogen-deficient ovariectomized rats showed significant mandibular bone loss that was reversed by systemic administration of sclerostin antibody (SAB) alone and in combination with DKK1 antibody (DAB). Osteocytes in the dentate and edentulous rat maxilla expressed Sost (sclerostin) and Dkk1 (DKK1) mRNA, and molar extraction appeared to acutely increase DKK1 expression. In a chronic rat maxillary molar extraction model, systemic SAB administration augmented the volume and height of atrophic alveolar ridges, effects that were enhanced by coadministering DAB. SAB and SAB+DAB also fully reversed bone loss that developed in the opposing mandible as a result of hypo-occlusion. In both treatment studies, alveolar bone augmentation with SAB or SAB+DAB was accompanied by increased bone mass in the postcranial skeleton. Jaw bone biomechanics showed that intact sclerostin-deficient mice exhibited stronger and denser mandibles as compared with wild-type controls. These studies show that sclerostin inhibition, with and without DKK1 coinhibition, augmented alveolar bone volume and architecture in rats with alveolar bone loss. These noninvasive approaches may have utility for the conservative augmentation of alveolar bone.

[Clinical significance of apolipoprotein B and AI determinations in coronary heart disease].

In this report, the relative validity of serum apolipoprotein (apo) B and AI analyses in the discrimination of coronary heart disease (CHD) was evaluated, and compared with the results of serum triglyceride (TG) total cholesterol, low density and high density lipoprotein cholesterol (HDL-C) determinations. 101 cases of CHD, 95 cases of myocardial infarction survivors (MIS) and 177 cases of acute myocardial infarction (AMI) were studied, with a control group including 266 age and sex matched healthy subjects. The results of monovariant statistics showed that apo B had highest percentage of positive results, and TG had most prominent elevation of mean values in CHD and MIS groups. Both multivariant stepwise discrimination and logistic regression analyses demonstrated the superiority of HDL-C, apo B and apo AI in detecting CHD in men; while in female subjects, apo B remained as the best discriminator, but apo AI and HDL-C lost its statistic significance. The quantitative relationships among apo AI, HDL-C and TG were discussed briefly. Since the decrease in HDL-C level in CHD were mainly due to hypertriglyceridemia, the significance of high TG level in correlation with CHD should not be neglected. AII serum lipids and apo B AI levels were decreased in AMI cases, and reached lowest values after 7 days. But the level of these variables were not changed significantly within 48 hours after onset of the episode. There was no frank correlation between the degree of serum lipid lowering and prognosis of AMI.

Cell surface activation of the erythropoietin receptor by Friend spleen focus-forming virus gp55.

The leukemogenic membrane glycoprotein gp55, encoded by Friend spleen focus-forming virus (SFFV), induces erythroid cell proliferation through its interaction with the erythropoietin receptor (EPO-R). There are two forms of gp55 in SFFV-infected cells: an intracellular form (more than 95% of the total protein), which is localized within the endoplasmic reticulum (ER) membranes, and a cell surface form (about 3 to 5%). Because both forms of the viral proteins bind to EPO-R, it is not clear whether the viral protein induces mitogenesis intracellularly or at the cell surface. To address this question, we constructed an EPO-R mutant that contained a 6-amino-acid (DEKKMP) C-terminus ER retention signal. Biochemical and functional analyses with this mutant indicated that it was completely retained in the ER and not expressed at the cell surface. Further analysis showed that the mutant, like the wild-type EPO-R, interacted with SFFV gp55. However, this apparent intracellular interaction between the two proteins failed to induce growth factor-independent proliferation of Ba/F3 cells. Furthermore, spontaneous variants of the ER-retained EPO-R selected on the basis of their ability to induce cell proliferation when coexpressed with gp55 were exclusively expressed at the cell surface. Thus, our results support the hypothesis that the mitogenic activation of the EPO-R by gp55 requires the interaction of the two proteins at the cell surface.