Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength

• Published in: eLife Vol. 12
• Main Authors: Leanza, Giulia, Cannata, Francesca, Faraj, Malak, Pedone, Claudio, Viola, Viola, Tramontana, Flavia, Pellegrini, Niccolò, Vadalà, Gianluca, Piccoli, Alessandra, Strollo, Rocky, Zalfa, Francesca, Beeve, Alec T, Scheller, Erica L, Tang, Simon Y, Civitelli, Roberto, Maccarrone, Mauro, Papalia, Rocco, Napoli, Nicola
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 10.04.2024; eLife Sciences Publications, Ltd
• Subjects: Advanced glycosylation end products; AGEs; Arthroplasty (hip); Biochemistry and Chemical Biology; bone; Bone and Bones; Bone growth; Bone histomorphometry; Bone mineral density; Bone strength; Cbfa-1 protein; Collagen; Collagen (type I); Correlation analysis; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Fasting; Female; Fractures; Gene expression; Glucose; histomorphometry; Humans; Hyperglycemia; Maillard Reaction; Mechanical properties; Medicine; Osteogenesis; Post-menopause; Research Personnel; SOST protein; Wnt protein; Wnt signaling; Wnt Signaling Pathway; Yield stress; histomorphometry; Wnt signaling; chemical biology; biochemistry; AGEs; bone; medicine; diabetes; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.90437

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes ( and ) 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 (p=0.0136) and (p=0.0302) were lower in T2D. Conversely, gene expression of (p=0.0232), (p<0.0001), and (p=0.0456) were higher, while collagen ( ) was lower in T2D (p=0.0482). AGEs content was associated with and (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with and (r=-0.7500, p=0.0255; r=-0.9762, p=0.0004). was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas and 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 (r=-0.5675, p=0.0011), (r=-0.5523, p=0.0042), and (r=-0.4442, p=0.0437), while positively correlated with (r=0.4116, p=0.0295) and (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.