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

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.

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

“…In contrast to glucose metabolism, deletion of osteogenic Dkk1 partially prevented T1DM-induced trabecular bone loss and completely prevented cortical bone loss. T1DM is known to reduce bone quantity and furthermore suppress the Wnt/β-catenin pathway 18,19,28,31,32 . Our results are consistent with another study postulating differential effects of β-catenin overexpression in mice with T1DM on trabecular and cortical bone 31 .…”

“…T1DM is known to reduce bone quantity and furthermore suppress the Wnt/β-catenin pathway 18,19,28,31,32 . Our results are consistent with another study postulating differential effects of β-catenin overexpression in mice with T1DM on trabecular and cortical bone 31 . Similar to our study, Wnt activation only ameliorated cortical, but not trabecular bone loss induced by T1DM, an effect the authors proposed to be dependent on differential Wnt16 expression.…”

β-Catenin mediates glucose-dependent insulinotropic polypeptide increases in lysyl oxidase expression in osteoblasts

“…Several recent studies have shown the dysregulation of β-catenin signaling in many tissues in diabetes, including in osteoblasts ( Yee et al, 2016 ; Chiang et al, 2012 ; Welters and Kulkarni, 2008 ; Jin, 2008 ). Reduced WNT/β-catenin signaling leads to impaired osteoblast activity in several mouse models of diabetes, including the streptozotocin (STZ)-induced T1DM mouse model used in our previous work ( Daley et al, 2019 ; Chen et al, 2018 ; Yee et al, 2016 ). Previous studies have shown that diabetic bone abnormalities resulting from T1DM more severely affect the trabecular rather than the cortical bone ( Daley et al, 2019 ; Shah et al, 2018 ; Jiang and Xia, 2018 ), and trabecular bone is known to be more readily affected by changes in β-catenin ( Li et al, 2017 ).…”

“…The canonical WNT pathway activates β-catenin signaling in osteoblasts and osteoblast precursor cells, and is essential for osteoblast differentiation and proliferation ( Monroe et al, 2012 ). Several recent studies have shown that WNT/β-catenin signaling is impaired in osteoblasts in T1DM rodent models, resulting in decreased osteoblast activity ( Chen et al, 2018 ; Yee et al, 2016 ). β-catenin promotes the transcription of target genes by complexing with TCF/LEF transcription factors ( Liu and Habener, 2008 ), and our laboratory has previously reported that there are functional TCF/LEF cis-elements in the lysyl oxidase promoter ( Khosravi et al, 2014 ).…”

An overview of de novo bone generation in animal models

“…Distinct from the amount of remodeled bone is the rate of trabecular or cortical bone turnover, often measured as the bone formation rate per unit of bone volume (BFR/BV) 146 . In humans, the BRF/BV is a well established measure 147,148 that is affected by age, 149 use, 42,150 and comorbidities 39,151,152 . In animal models, it is used to assess both the rate of bone remodeling and bone healing 153 .…”