Increased bone inflammation in type 2 diabetes and obesity correlates with Wnt signaling downregulation and reduced bone strength

Abstract Type 2 diabetes (T2D) and obesity (OB) are associated with chronic low-grade inflammation and increased fracture risk. In vitro studies showed that inflammation induces bone erosion and inhibits bone formation by increasing Wnt canonical pathway inhibitors. However, the impact of inflammation on Wnt pathway regulation and bone quality in T2D and OB remains unclear. To this end, we studied 63 postmenopausal women (age >65 years) undergoing hip replacement for osteoarthritis. Among these women, 19 had T2D and OB (HbA1c 6.8±0.79%; BMI 29.9±5.2 kg/m2), 17 had OB but they were normoglycemic (BMI 32.5±5.4 kg/m2), and 27 served as controls (BMI 23.1±5.5 kg/m2). Serum inflammatory cytokines by automated immunoassay (ELLA), revealed higher TNF-α (p=0.0084) and lower adiponectin (p=0.0402) in T2D, and higher IL-6 (p=0.0003) levels in OB vs controls. Gene expression analysis of trabecular bone showed increased TNF-α (p=0.0019) and SFRP5 (p=0.0084) in T2D vs controls. IL-10 was lower in both T2D (p=0.0285), and OB (p=0.0324), while adiponectin (ADIPOQ) was only lower in T2D (p=0.0041) vs controls. Interestingly, the Wnt inhibitor SOST was higher in T2D (p<0.0001) and OB (p<0.0001) vs controls. Conversely, WNT10B mRNA levels were lower in T2D (p=0.0071) and in OB (p=0.0196) vs controls, while LEF-1 were only lower in T2D (p=0.0009). WNT5A (p=0.0025) and GSK3β (p=0.0003) mRNA levels were higher only T2D vs controls. Importantly, TNF-α mRNA levels positively correlated with SOST (r=0.5121, p=0.0002), WNT5A (r=0.3227, p=0.0396) and GSK3β (r=0.3789, p=0.0146) mRNA levels, but negatively correlated with WNT10B (r=0.3844, p=0.0188) and LEF-1(r=-0.3310, p=0.0322) mRNA levels. Conversely, IL-10 was negatively correlated with SOST mRNA levels (r=0.3100, p=0.0457). ADIPOQ was negatively correlated with SOST (r=-0.3864, p=0.0105) and WNT5A (r=-0.3025, p=0.0515) mRNA levels. Moreover, SFRP5 was negatively correlated with LEF-1 mRNA levels (r=0.3991, p=0.0131). Finally, serum levels of TNF-α (r=-0.3473, p=0.0352) and IL-6 (r=-0.3777, p=0.0302) negatively correlated with Young’s Modulus, an index of bone strength. These findings suggest that increased inflammation in bone of subjects with T2D and obesity is negatively associated with Wnt pathway and bone strength, shedding light on pathophysiology of bone impairment in T2D and obesity.