Increased circulating sclerostin levels and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Recent data from our group have shown that T2D affects the expression of genes controlling bone formation (SOST and RUNX2) and that accumulation of AGEs is associated with impaired bone microarchitecture. Whether the expression of the Wnt beta-catenin target genes is altered in T2D, and whether AGEs accumulation it is associated with type 1 Collagen (COL1A1) alteration is still unknown. We hypothesized that increased SOST gene expression leads to downregulation of Wnt β- catenin target genes (TCF/LEF1) and AGEs accumulation is related to a downregulation of COL1A1 in bones from subjects with T2D. We analyzed bone tissue from femoral heads of 14 T2D postmenopausal women (mean HbA1c 6.5%) and 21 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. We found that TCF-LEF1 was significantly lower in T2D compared to non- diabetic subjects (p=0.0092). Dickkopf -1 (DKK-1), the other inhibitor of beta-catenin-dependent Wnt signalling besides sclerostin, was not different between groups (p=0.1083). However, analysis of correlation showed that DKK-1 increases with age (r2=0.038; p=0.043) and HbA1c (r2=0.503; p=0.048) in T2D subjects. COL1A1 gene expression was lower in T2D compared to controls although significance was not fully reached (p=0.0564). Importantly, AGEs bone content was significantly higher in T2D compared to nondiabetics (1.5 fold increase; p<0.0001).
In conclusion, our data show that even in patients with relatively good glycemic control, T2D affects the expression of collagen and Wnt beta-catenin target genes. We also found that accumulation of AGEs is possibly associated with alteration in collagen gene expression. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D.
G. Leanza: None. F. Tramontana: None. F. Cannata: None. A. Piccoli: None. M. Faraj: None. V. Viola: None. R. Strollo: None. N. Napoli: None. P. Pozzilli: None.
Campus Bio-Medico University