Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher Advanced Glycation End-products (AGEs) content and reduced bone strength

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes ( SOST and RUNX2 ) and Advanced Glycation End-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D [(T2D 0.249% (0.156-0.366) vs non-diabetic subjects 0.352% (0.269-0.454); p=0.053)], as well as reduced bone strength [T2D 21.60 MPa (13.46-30.10) vs non-diabetic subjects 76.24 MPa (26.81-132.9); p=0.002]. We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001) and GSK3B (p=0.0456) were higher, while collagen ( COL1A1 ) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r= -0,7500, p=0.0255; r= -0,9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s Modulus was negatively correlated with SOST (r=-0.5675, p=0.0011), AXIN2 (r=-0.5523, p=0.0042) and SFRP5 (r=-0.4442, p=0.0437), while positively correlated with LEF -1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling, and AGEs could be the main determinants of bone fragility in T2D. Graphical abstract