Osteoporosis is a common systemic skeletal disorder that leads to increased bone fragility and increased risk of fracture. Although βII-Spectrin (SPTBN1) has been reported to be involved in the development of various human cancers, the function and underlying molecular mechanisms of SPTBN1 in primary osteoporosis remain unclear. In this study, we first established a primary osteoporosis mouse model of senile osteoporosis and postmenopausal osteoporosis. The results showed that the expression of SPTBN1 was significantly downregulated in primary osteoporosis mice model compared with the control group. Furthermore, silencing of SPTBN1 led to a decrease in bone density, a small number of trabecular bones, wider gap, decreased blood volume fraction and number of blood vessels, as well as downregulation of runt-related transcription factor 2 (Runx2), Osterix (Osx), Osteocalcin (Ocn), and vascular endothelial growth factor (VEGF) in primary osteoporosis mice model compared with the control group. Besides, the silencing of SPTBN1 inhibited the growth and induced apoptosis of mouse pre-osteoblast MC3T3-E1 cells compared with the negative control group. Moreover, the silencing of SPTBN1 significantly increased the expression of TGF-β, Cxcl9, and the phosphorylation level STAT1 and Smad3 in MC3T3-E1 cells compared with the control group. As expected, overexpression of SPTBN1 reversed the effect of SPTBN1 silencing in the progression of primary osteoporosis both in vitro and in vivo. Taken together, these results suggested that SPTBN1 suppressed primary osteoporosis by facilitating the proliferation, differentiation, and inhibition of apoptosis in osteoblasts via the TGF-β/Smad3 and STAT1/Cxcl9 pathways. Besides, overexpression of SPTBN1 promoted the formation of blood vessels in bone by regulating the expression of VEGF. This study, therefore, provided SPTBN1 as a novel therapeutic target for osteoporosis.
diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic β-cells. This dysfunction is partly caused by the dysregulation of pyruvate dehydrogenase (PdH), which acts as an important mediator of pyruvate oxidation after glycolysis and fuels the tricarboxylic acid cycle. Previous studies have reported decreased PdH expression in rodent models and humans with type 2 diabetes mellitus (T2dM), suggesting that PdH may play an important role in the development of T2dM. However, the mechanism by which PdH affects insulin secretion and β-cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase e1-α subunit (PdHa1; encoded by the PDHA1 gene) in the islets of type 2 diabetic mice (db/db mice) was lower than in wild-type mice, which indicated the possible association between PdHa1and diabetes. To further understand this mechanism, an inducible, islet-specific PdHa1 knockout mouse (βKo) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the βKo and control mice were compared. Though no changes were found in food intake, development status, fasting blood glucose or weight between the groups, the level of insulin secretion at 30 min after glucose injection in the βKO group was significantly lower compared with the control group. Furthermore, the performed of the βKo mice on the intraperitoneal glucose tolerance test was visibly impaired when compared with the control mice. Pancreatic tissues were collected for hematoxylin and eosin staining, immunohistochemical and confocal laser-scanning microscopy analysis. examination of the islets from the βKo mouse model indicated that abolishing the expression of PdH caused a compensatory islet enlargement and impaired insulin secretion.
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