Xie Xudong, Hu Liangcong, Mi Bobin, Panayi Adriana C, Xue Hang, Hu Yiqiang, Liu Guodong, Chen Lang, Yan Chenchen, Zha Kangkang, Lin Ze, Zhou Wu, Gao Fei, Liu Guohui
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China.
Front Cell Dev Biol. 2022 Apr 4;10:826023. doi: 10.3389/fcell.2022.826023. eCollection 2022.
With the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies. In this study, we investigated the use of AQX-1125, a novel clinical-stage activator of inositol phosphatase-1 (SHIP1), in ovariectomized (OVX) mice, identifying a protective role. We then found that the effect was likely due to increased osteogenesis and mineralization and decreased osteoclastogenesis caused by AQX-1125 in a time- and dose-dependent manner. The effect against OVX-induced bone loss was identified to be SHIP1-dependent as pretreatment of BMSCs and BMMs with SHIP1 RNAi could greatly diminish the osteoprotective effects. Furthermore, SHIP1 RNAi administration induced significant bone loss and decreased bone mass. Mechanistically, AQX-1125 upregulated the expression level and activity of SHIP1, followed upregulating the phosphorylation levels of PI3K and Akt to promote osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN). NF-κB signaling was also inhibited through suppression of the phosphorylation of IκBα and P65 induced by RANKL, resulting in diminished osteoclastogenesis. Taken together, our results demonstrate that AQX-1125 may be a promising candidate for preventing and treating bone loss.
随着全球人口老龄化，骨质疏松症的患病率正在上升，尤其是患有这种疾病的绝经后女性的数量。然而，目前可用治疗方案所伴随的各种不良副作用凸显了开发新疗法的必要性。在本研究中，我们研究了新型临床阶段肌醇磷酸酶 -1（SHIP1）激活剂AQX - 1125在去卵巢（OVX）小鼠中的应用，确定了其保护作用。然后我们发现这种作用可能是由于AQX - 1125以时间和剂量依赖性方式增加了成骨作用和矿化作用，并减少了破骨细胞生成。针对OVX诱导的骨质流失的作用被确定为依赖SHIP1，因为用SHIP1 RNAi预处理骨髓间充质干细胞（BMSCs）和骨髓巨噬细胞（BMMs）可大大减弱骨保护作用。此外，给予SHIP1 RNAi会导致明显的骨质流失和骨量减少。从机制上讲，AQX - 1125上调了SHIP1的表达水平和活性，随后上调了PI3K和Akt的磷酸化水平，以促进包括碱性磷酸酶（Alp）、核心结合因子α1（cbfa1）、I型胶原α1（Col1a1）和骨钙素（OCN）在内的成骨细胞相关基因的表达。通过抑制RANKL诱导的IκBα和P65的磷酸化，NF - κB信号传导也受到抑制，从而减少破骨细胞生成。综上所述，我们的结果表明AQX - 1125可能是预防和治疗骨质流失的一个有前景的候选药物。
