Differential effects of type 1 diabetes mellitus and subsequent osteoblastic \u03b2-catenin activation on trabecular and cortical bone in a mouse model

Sixu Chen,Quanwei Bao,Yufeng Zhao,Daocheng Liu,Huayu Liu,Lei Yang,Zhaowen Zong,Sihao He,Hao Qin

doi:10.1038/s12276-018-0186-y

Abstract

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.

Highlights

The autoimmune destruction of insulin-producing βcells in the pancreas causes type 1 diabetes mellitus (T1DM)
The trabecular parameters were significantly lower in the T1DM mice than those in the control mice, whereas the corresponding cortical parameters decreased to a substantially less extent in the T1DM mice compared with the control mice
Osteoblastic activation of β-catenin in T1DM mice abrogated bone loss and improved bone strength in the trabecular bone Because the downregulation of WNT/β-catenin signaling may be a crucial factor in T1DM-induced bone loss, we subsequently investigated whether the activation of βcatenin increases the bone mass in T1DM mice. βCatenin was conditionally activated in osteoblasts of Col1-3.2kb-CreERTM; Catnblox(ex3) mice by injecting tamoxifen

Summary

Introduction

The autoimmune destruction of insulin-producing βcells in the pancreas causes type 1 diabetes mellitus (T1DM). This leads to complete insulin deficiency and a concomitant disruption of glucose homeostasis. T1DM patients have twice the risk of any fracture and a 4–5-fold greater risk of hip fracture than individuals without diabetes[1]. The canonical WNT signaling pathway regulates gene transcription by stabilizing β-catenin, and it has been implicated in a wide range of physiological and pathophysiological processes[5,6]. Accumulating evidence suggests that the interactions between glucose metabolism and WNT/β-catenin signaling are reciprocal. Several studies have suggested the potential involvement of WNT

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