Comprehensive transcriptome analysis of mesenchymal stem cells in elderly patients with osteoporosis.

OBJECTIVE: To explore the role of aging in the pathogenesis of osteoporosis, several differentially expressed genes (DEGs) and altered biological pathways were identified in mesenchymal stem cells (MSCs) in elderly patients with osteoporosis. METHODS: Raw data were downloaded from Gene Expression Omnibus database. A total of 14 human MSC samples were available, including five samples from elderly patients suffering from osteoporosis, five controls from young non-osteoporotic donors and five controls from old non-osteoporotic donors. The DEGs were identified using LIMMA package among the three groups. Gene ontology and KEGG pathway analysis were carried out using DAVID. A protein-protein interaction (PPI) network of DEGs was constructed with STRING and then visualized with Cytoscape. RESULTS: A total of 3179 DEGs were screened, including 1071 up- and 2108 down-regulated genes. Compared with young and old controls, 271 and 781 genes were up-regulated in osteoporosis, respectively, and 17 genes were shared. Function and pathway enrichment showed that the up-regulated genes in osteoporosis were involved in extracellular matrix (ECM)-receptor interaction, focal adhesion and mammalian target of rapamycin signaling pathway. Moreover, a range of genes linked to cell adhesion, ECM-receptor interaction and cell cycle were revealed in the PPI network, such as transforming growth factor beta 1, insulin-like growth factor 2 and integrin beta 2. CONCLUSION: A number of DEGs and altered pathways were screened in osteoporosis. Our study provided insights into the role of aging in the pathogenesis of osteoporosis and some DEGs might be potential biomarkers for osteoporosis.

The relationship among renal injury, changed activity of renal 1-alpha hydroxylase and bone loss in elderly rats with insulin resistance or Type 2 diabetes mellitus.

BACKGROUND AND OBJECTIVE: Chronic kidney disease can lead to a decrease in active vitamin D [1,25-(OH)2D], which may be reversed by 1-alpha hydroxyvitamin D [1-alpha(OH)D]. Renal 1-alpha hydroxylase, expressed in renal tubular epithelial cells, is a key enzyme in the synthesis of 1,25-(OH)2D. 1,25- (OH)2D plays an important role in the regulation of calcium and phosphate metabolism, and its deficiency can result in osteoporosis. Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are associated with renal injury, decrease in 1,25-(OH)2D and bone loss. The study aimed to explore the relationship among renal injury, decrease in 1,25-(OH)2D and bone loss in the presence of IR or T2DM, as well as the role of renal 1-alpha hydroxylase in the process. MATERIALS AND METHODS: Fifty 18-month-old male Wistar rats were randomized into 5 groups: normal control group (Group N), IR group (Group I), T2DM group (Group D), No.1 treatment group (Group T1), and No.2 treatment group (Group T2), 10 in each group. High-fat diet was administered to induce IR, while high-fat diet and low-dose streptozotocin were jointly applied to induce T2DM. Rats in Groups T1 and T2 were treated with vitamin D and 1-alpha(OH)D, respectively. At week 12, IR was determined by the use of euglycemic insulin clamp technique for rats in each group, and then glucose infusion rate (GIR) was calculated. Meanwhile, urinary albumin (UA), serum 25-(OH)D and 1,25-(OH)2D levels were determined by radioimmunoassay. After the rats were sacrificed, bone mineral density (BMD) in femoral bone and lumbar vertebrae was measured by the use of dual energy X-ray absorption. RESULTS: The GIR in Group N was significantly higher than that of the other 4 groups (p<0.01). Compared with Groups N (p<0.01) or I (p<0.05), the UA levels in Groups D, T1, and T2 were obviously higher. The UA level in Group I was higher than that of Group N, but the difference was not significant (p>0.05). In Groups D and I, the UA levels showed a negative correlation with GIR. No significant difference was observed in the levels of 25-hydroxyvitamin D [25-(OH)D]. The levels of 1,25-(OH)2D in Groups D and T1 were markedly lower than that of Groups N or T2 (p<0.01). The 1,25-(OH)2D level in Group I was lower than that of Group N (p<0.05), but higher than that of Group D (p<0.01). The 1,25-(OH)2D level in Group T2 was nearly equivalent to that of Group N. In Groups D and I, the levels of 1,25-(OH)2D were negatively correlated with UA, and positively correlated with GIR. The BMD levels in lumbar vertebrae or femoral bone in Groups D and T1 were similar, but both were lower than that of Groups T2 (p<0.05) and N (p<0.01). The BMD levels were lower in Groups I and T2 compared with that of Group N (p<0.05), but higher than that of Groups D and T1 (p<0.05). The BMD levels in lumbar vertebrae or femoral bone in Groups I and D were positively correlated with GIR. The BMD level in lumbar vertebrae or femoral bone in Group D showed negative correlation with UA. CONCLUSION: In elderly rats with T2DM or IR, renal injury may cause decreased activity of renal 1-alpha hydroxylase, which may result in bone loss and disturbance in VD metabolism, mainly manifesting as a significant reduction in the 1,25-(OH)2D level.

The relationship between renal injury and change in vitamin D metabolism in aged rats with insulin resistance or type 2 diabetes mellitus.

Insulin resistance (IR), IR treated with vitamin D, IR treated with 1alpha-hydroxyvitamin D (1alpha-(OH)D), type 2 diabetes mellitus (T2DM), T2DM treated with vitamin D and T2DM treated with 1alpha-(OH)D were studied in animal models using aged Wistar rats. Glucose infusion rates and levels of urinary albumin (UA), serum 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. T2DM rats had higher UA than IR or normal rats, and levels of 25-(OH)D in all models weresimilar. IR rats had higher 1,25-(OH)2D levels than T2DM rats, and had lower 1,25-(OH)2D levels than normal rats. Treating IR or T2DM rats with vitamin D had no effect on 25-(OH)D or 1,25-(OH)2D. Administration of 1alpha-(OH)D significantly increased 1,25-(OH)2D in IR rats to above-normal levels, and significantly increased 1,25-(OH)2D in T2DM rats to normal levels. In IR or T2DM, abnormal vitamin D metabolism is characterized by 1,25-(OH)2D deficiency and is related to renal injury.