PTP1B knockdown alleviates BMSCs senescence via activating AMPK-mediated mitophagy and promotes osteogenesis in senile osteoporosis
PTP1B knockdown alleviates BMSCs senescence via activating AMPK-mediated mitophagy and promotes osteogenesis in senile osteoporosis
复制标题
DOI：
10.1016/j.bbadis.2023.166795
复制
发表时间：
2023-07-04
影响因子：
6.2
通讯作者：
Luo，Fei
中科院分区：
文献类型：
--
作者：
Yang，QianKun;Zou，YuChi;Luo，Fei
骨髓间充质干细胞的衰老是老年性骨质疏松症的基础。针对BMSCs的衰老对于制定抗骨质疏松的策略至关重要。在本研究中，我们发现蛋白酪氨酸磷酸酶1B(PTP1B)是一种负责酪氨酸去磷酸化的酶，随着年龄的增加，BMSCs和股骨中的蛋白酪氨酸磷酸酶1B显著上调。因此，我们研究了PTP1B在BMSCs衰老和老年性骨质疏松症中的作用。首先，在D-半乳糖(D-Gal)诱导的BMSCs和自然老化的BMSCs中，PTP1B的表达显著上调，成骨分化能力减弱。此外，PTP1B沉默可有效延缓衰老，改善线粒体功能障碍，恢复成骨分化，其机制可能与PKM2/AMPK通路介导的吞噬作用增强有关。此外，自噬抑制剂羟基氯喹(HCQ)显著逆转了PTP1B基因敲除的保护作用。在SOP动物模型中，移植LVsh-PTP1B基因修饰的D-Gal诱导的BMSCs具有促进骨形成和减少破骨细胞生成的双重保护作用。类似地，HCQ处理显著抑制了LVsh-PTP1B基因修饰的D-Gal诱导的BMSCs的体内成骨。综上所述，我们的数据表明，PTP1B沉默可以防止BMSCs衰老，并通过激活AMPK介导的有丝分裂来减轻SOP。靶向PTP1B可能是一种有希望的减轻SOP的介入策略。
The senescence of bone marrow mesenchymal stem cells (BMSCs) is the basis of senile osteoporosis (SOP). Targeting BMSCs senescence is of paramount importance for developing anti-osteoporotic strategy. In this study, we found that protein tyrosine phosphatase 1B (PTP1B), an enzyme responsible for tyrosine dephosphorylation, was significantly upregulated in BMSCs and femurs with advancing chronological age. Therefore, the potential role of PTP1B in BMSCs senescence and senile osteoporosis was studied. Firstly, significantly upregulated PTP1B expression along with impaired osteogenic differentiation capacity was observed in D-galactose (D-gal)-induced BMSCs and naturally-aged BMSCs. Furthermore, PTP1B silencing could effectively alleviate senescence, improve mitochondrial dysfunction, and restore osteogenic differentiation in aged BMSCs, which was attributable to enhanced mitophagy mediated by PKM2/AMPK pathway. In addition, hydroxychloroquine (HCQ), an autophagy inhibitor, significantly reversed the protective effects from PTP1B knockdown. In SOP animal model, transplantation of LVsh-PTP1B-transfected D-gal-induced BMSCs harvested double protective effects, including increased bone formation and reduced osteoclastogenesis. Similarly, HCQ treatment remarkably suppressed osteogenesis of LVsh-PTP1B-transfected D-gal-induced BMSCs in vivo. Taken together, our data demonstrated that PTP1B silencing protects against BMSCs senescence and mitigates SOP via activating AMPK-mediated mitophagy. Targeting PTP1B may represent a promising interventional strategy to attenuate SOP.