Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy; Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
Francesca Cannata
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Malak Faraj
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Claudio Pedone
Operative Research Unit of Geriatrics, Fondazione Policlinico Universitario Campus Bio Medico, Via Alvaro del Portillo, Roma, Italy
Viola Viola
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Flavia Tramontana
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy; Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Gianluca Vadalà
Operative Research Unit of Orthopedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
Alessandra Piccoli
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Rocky Strollo
Department of Human Sciences and Promotion of the Quality of Life San Raffaele Roma Open University Via di Val Cannuta, Roma, Italy
Francesca Zalfa
Predictive Molecular Diagnostic Unit, Pathology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy; Microscopic and Ultrastructural Anatomy Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
Alec T Beeve
Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, United States
Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, United States
Simon Y Tang
Department of Orthopaedic Surgery, Washington University in St. Louis, St Louis, United States
Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, United States
Mauro Maccarrone
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio snc, Aquila, Italy; European Center for Brain Research, Santa Lucia Foundation IRCCS, Roma, Italy
Rocco Papalia
Operative Research Unit of Orthopedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
Department of Medicine and Surgery, Research Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy; Operative Research Unit of Osteometabolic and Thyroid Diseases, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy; Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, United States
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.
