Bone inflammation in postmenopausal women with type 2 diabetes or obesity in relation to Wnt signaling and bone strength.

Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in subjects with T2D or OB. This study involved 63 postmenopausal women (aged ≥65 years) undergoing hip arthroplasty, including 19 with T2D, 17 with OB, and 27 controls (CTRL). We assessed body composition using dual-energy X-ray absorptiometry (DXA), bone microarchitecture with microcomputed tomography (μCT), and bone strength through compression tests. Bone tissue was collected for gene and protein expression analysis, and serum samples were obtained for cytokine measurement. Bone gene expression analysis revealed increased tumor necrosis factor-alpha (TNF-α; p < 0.0001) and reduced adiponectin (ADIPOQ; p = 0.0041) in T2D. Secreted frizzled-related protein 5 (SFRP5) was elevated in both T2D (p < 0.0001), whereas the OB group showed only a trend toward higher expression (p = 0.060) after BMI adjustment. Interleukin-10 (IL10) was reduced in both T2D (p = 0.0005), while in the OB group IL10 was not reduced after BMI adjustment. Importantly, the Wnt inhibitor sclerostin (SOST) was elevated in both T2D and OB subjects (p < 0.0001), while wingless-type family member 10B (WNT10B) and lymphoid enhancer-binding factor 1 (LEF1) were reduced in both T2D (WNT10B: p = 0.0070, LEF1: p < 0.0001) and OB (WNT10B: p = 0.0078, LEF1: p = 0.0199), even after BMI adjustment. Protein expression analysis by immunohistochemistry confirmed reduced non-phosphorylated (active) β-catenin in bone tissue of both T2D and OB subjects. Moreover, key inflammatory markers were associated with alterations in Wnt pathway-related genes. Consistently, serum cytokine analysis showed increased inflammation, with higher TNF-α (p = 0.0084) and lower ADIPOQ (p = 0.0402) levels in T2D, and higher interleukin-6 (IL-6; p = 0.0003) in OB compared to CTRL. Finally, serum TNF-α (r = -0.3557, p = 0.0112) and IL-6 (r = -0.3881, p = 0.0194) levels negatively correlated with bone strength. In conclusion, our results suggest that T2D is associated with increased bone inflammation, and Wnt signaling is downregulated in both T2D and obesity. These observations lay the groundwork for future mechanistic studies on bone fragility in metabolic diseases.