State Key Laboratory of Trauma, Burn and Combined Injury, Department of War Wound Rescue Skills Training, Base of Army Health Service Training, Army Medical University, Chongqing, China.
Department of Orthopedics, The 118th Hospital of the Chinese People's Liberation Army, Zhejiang, Wenzhou, China.
J Cell Physiol. 2020 Feb;235(2):1480-1493. doi: 10.1002/jcp.29068. Epub 2019 Jul 12.
Type 1 diabetes (T1D) is correlated with osteopenia primarily due to low bone formation. Parathyroid hormone (PTH) is a known anabolic agent for bone, the anabolic effects of which are partially mediated through the Wnt/β-catenin signaling pathway. In the present study, we first determined the utility of intermittent PTH treatment in a streptozotocin-induced T1D mouse model. It was shown that the PTH-induced anabolic effects on bone mass and bone formation were attenuated in T1D mice compared with nondiabetic mice. Further, PTH treatment failed to activate β-catenin signaling in osteoblasts of T1D mice and was unable to improve osteoblast proliferation and differentiation. Next, the Col1-3.2 kb-CreERTM; β-cateninfx(ex3) mice were used to conditionally activate β-catenin in osteoblasts by injecting tamoxifen, and we addressed whether or not preactivation of β-catenin boosted the anabolic action of PTH on T1D-related bone loss. The results demonstrated that pretreatment with activation of osteoblastic β-catenin followed by PTH treatment outperformed PTH or β-catenin activation monotherapy and led to greatly improved bone structure, bone mass, and bone strength in this preclinical model of T1DM. Further analysis demonstrated that osteoblast proliferation and differentiation, as well as osteoprogenitors in the marrow, were all improved in the combination treatment group. These findings indicated a clear advantage of developing β-catenin as a target to improve the efficacy of PTH in the treatment of T1D-related osteopenia.
1 型糖尿病（T1D）与低骨形成有关，主要导致骨质疏松症。甲状旁腺激素（PTH）是一种已知的骨骼合成代谢药物，其合成代谢作用部分通过 Wnt/β-catenin 信号通路介导。在本研究中，我们首先确定了间歇性 PTH 治疗在链脲佐菌素诱导的 T1D 小鼠模型中的应用。结果表明，与非糖尿病小鼠相比，T1D 小鼠的 PTH 对骨量和骨形成的合成代谢作用减弱。此外，PTH 治疗未能激活 T1D 小鼠成骨细胞中的 β-catenin 信号通路，也无法改善成骨细胞的增殖和分化。接下来，使用 Col1-3.2kb-CreERTM;β-cateninfx(ex3) 小鼠通过注射他莫昔芬条件性激活成骨细胞中的 β-catenin，我们研究了预先激活 β-catenin 是否可以增强 PTH 对 T1D 相关骨丢失的合成代谢作用。结果表明，成骨细胞中β-catenin 的预先激活，然后再进行 PTH 治疗，优于 PTH 或β-catenin 激活单药治疗，在这种 T1DM 的临床前模型中导致骨结构、骨量和骨强度得到极大改善。进一步分析表明，在联合治疗组中，成骨细胞增殖和分化以及骨髓中的成骨前体细胞均得到改善。这些发现表明，将β-catenin 作为靶点开发以提高 PTH 治疗 T1D 相关骨质疏松症的疗效具有明显优势。
