Differential effects of type 1 diabetes mellitus and subsequent osteoblastic β-catenin activation on trabecular and cortical bone in a mouse model

Type 1 diabetes mellitus (T1DM) is a pathological condition associated with osteopenia. WNT/β-catenin signaling is implicated in this process. Trabecular and cortical bone respond differently to WNT/β-catenin signaling in healthy mice. We investigated whether this signaling has different effects on trabecular and cortical bone in T1DM. We first established a streptozotocin-induced T1DM mouse model and then constitutively activated β-catenin in osteoblasts in the setting of T1DM (T1-CA). The extent of bone loss was greater in trabecular bone than that in cortical bone in T1DM mice, and this difference was consistent with the reduction in the expression of β-catenin signaling in the two bone compartments. Further experiments demonstrated that in T1DM mice, trabecular bone showed lower levels of insulin-like growth factor-1 receptor (IGF-1R) than the levels in cortical bone, leading to lower WNT/β-catenin signaling activity through the inhibition of the IGF-1R/Akt/glycogen synthase kinase 3β (GSK3β) pathway. After β-catenin was activated in T1-CA mice, the bone mass and bone strength increased to substantially greater extents in trabecular bone than those in cortical bone. In addition, the cortical bone of the T1-CA mice displayed an unexpected increase in bone porosity, with increased bone resorption. The downregulated expression of WNT16 might be responsible for these cortical bone changes. In conclusion, we found that although the activation of WNT/β-catenin signaling increased the trabecular bone mass and bone strength in T1DM mice, it also increased the cortical bone porosity, impairing the bone strength. These findings should be considered in the future treatment of T1DM-related osteopenia. Diabetes: Bone types respond differently to potential intervention Activation of a key signaling pathway implicated in bone mass maintenance helps boost the strength of spongy internal bone in a mouse model of type 1 diabetes mellitus (T1DM) but also increases the porosity of the outer surface, compromising bone integrity. Zhaowen Zong and colleagues from the Army Medical University in ChongQing, China experimentally induced T1DM in mice and saw greater loss of inner ‘trabecular’ bone than outer ‘cortical’ bone. Looking to improve bone strength, the researchers genetically activated a key signaling pathway by boosting β-catenin levels in bone-forming osteoblast cells. This intervention had different effects on the two bone types, with increased mass and strength in t