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Purpose: Increasing evidence supported that semaphorin 3A (Sema3A), insulin-like growth factor (IGF)-1 and β-catenin were involved in the development of osteoporosis and diabetes. This study is aimed to evaluate whether Sema3A/IGF-1/β-catenin is directly involved in the alterations of bone microarchitecture and bone strength of diabetic rats. Methods: Diabetic rats were induced by streptozotocin and high fat diet exposure. Bone microarchitecture and strength in the femurs were evaluated by micro-CT scanning, three-point bending examination and the stainings of HE, alizarin red S and safranin O/fast green, respectively. The alterations of lumbar spines microarchitecture were also determined by micro-CT scanning. Western blot and immunohistochemical analyses were used to examine the expression of Sema3A, β-catenin, IGF-1, peroxisome proliferator-activated receptor γ (PPARγ) and cathepsin K in rat tibias. Results: Diabetic rats exhibited decreased trabecular numbers and bone formation, but an increased trabecular separation in the femurs and lumbar spines. Moreover, the increased bone fragility and decreased bone stiffness were evident in the femurs of diabetic rats. Diabetic rats also exhibited a pronounced bone phenotype which manifested by decreased expression of Sema3A, IGF-1 and β-catenin, as well as increased expression of cathepsin K and PPARγ. Conclusions: This study suggests that diabetes could perturb bone loss through the Sema3A/IGF-1/β-catenin pathway. Sema3A deficiency in bone may contribute to upregulation of PPARγ and cathepsin K expression, which further disrupts bone remodeling in diabetic rats. [ABSTRACT FROM AUTHOR]

Human cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Although its collagenase activity is unique, CatK also exerts a potent elastolytic activity that is shared with human cathepsins V and S. Other members of the cysteine cathepsin family, which are structurally similar, do not exhibit significant collagen and elastin degrading activities. This raises the question of the presence of specific structural elements, exosites, that are required for these activities. CatK has two exosites that control its collagenolytic and elastolytic activity. Modifications of exosites 1 and 2 block the elastase activity of CatK, whereas only exosite-1 alterations prevent collagenolysis. Neither exosite affects the catalytic activity, protease stability, subsite specificity of CatK or the degradation of other biological substrates by this protease. A low-molecular-mass inhibitor that docks into exosite-1 inhibits the elastase and collagenase activity of CatK without interfering with the degradation of other protein substrates. The identification of CatK exosites opens up the prospect of designing highly potent inhibitors that selectively inhibit the degradation of therapeutically relevant substrates by this multifunctional protease. [ABSTRACT FROM AUTHOR]

The article presents a study that examines the accumulation of free cholesterol in macrophage membranes. Result of the study shows that macrophages from knockout mice showed important role for Toll-like receptor (TLR) 4 and TLR3 after late endosomal loading. The study suggests that free cholesterol enrichment of either plasma and endosomal membrane in macrophages leads to activation of various TLRs and prolonged p38 nitrogen-activated protein kinase as well as the induction of Cathepsin K(Ctsk).