Abstract
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Loss-of-function variants of low-density lipoprotein receptor-related protein 5 (LRP5) can lead to reduced bone formation, culminating in diminished bone mass. Our previous study reported transcription factor osterix (SP7)-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration. However, the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown. In this study, we used mice with a conditional knockout (cKO) of LRP5 in mature osteoblasts, which presented decreased osteogenesis. The in vitro experimental results showed that SP7 could promote LRP5 expression, thereby upregulating the osteogenic markers such as alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and β-catenin (P<0.05). For the in vivo experiment, the SP7 overexpression virus was injected into a bone defect model of LRP5 cKO mice, resulting in increased bone mineral density (BMD) (P<0.001) and volumetric density (bone volume (BV)/total volume (TV)) (P<0.001), and decreased trabecular separation (Tb.Sp) (P<0.05). These data suggested that SP7 could ameliorate bone defect healing in LRP5 cKO mice. Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.
低密度脂蛋白受体相关蛋白5（LRP5）的功能丧失突变将导致骨形成减少，从而最终导致低骨量的表型。先前研究报道了LRP5启动子存在转录因子SP7的结合位点。此外，SP7在种植体骨整合过程中具有上调LRP5表达的关键作用。但SP7在改善LRP5缺失所致骨质疏松的作用机制尚不明确。本研究使用成骨细胞LRP5条件性缺失小鼠展开相关研究，该小鼠具有骨质疏松表型。细胞实验结果表明，SP7可促进LRP5表达并上调包括碱性磷酸酶（ALP）、Runt相关转录因子2（Runx2）和β-catenin等成骨相关基因的表达（P<0.05）。体内实验将SP7过表达慢病毒注射到LRP5条件性敲除小鼠骨缺损区域，愈合4周后，与对照组相比，SP7治疗组骨密度（BMD）（P<0.001）和骨体积分数（BV/TV）（P<0.001）显著升高，而骨小梁分离系数（Tb.Sp）显著减小（P<0.05）。上述数据表明，SP7可改善LRP5条件性缺失所致小鼠骨质疏松的骨缺损愈合过程。该研究为改善LRP5缺失所致骨质疏松提供了潜在治疗策略。.
低密度脂蛋白受体相关蛋白5（LRP5）的功能丧失突变将导致骨形成减少，从而最终导致低骨量的表型。先前研究报道了LRP5启动子存在转录因子SP7的结合位点。此外，SP7在种植体骨整合过程中具有上调LRP5表达的关键作用。但SP7在改善LRP5缺失所致骨质疏松的作用机制尚不明确。本研究使用成骨细胞LRP5条件性缺失小鼠展开相关研究，该小鼠具有骨质疏松表型。细胞实验结果表明，SP7可促进LRP5表达并上调包括碱性磷酸酶（ ALP）、Runt相关转录因子2（ Runx2）和β-catenin等成骨相关基因的表达（ P<0.05）。体内实验将SP7过表达慢病毒注射到LRP5条件性敲除小鼠骨缺损区域，愈合4周后，与对照组相比，SP7治疗组骨密度（BMD）（ P<0.001）和骨体积分数（BV/TV）（ P<0.001）显著升高，而骨小梁分离系数（Tb.Sp）显著减小（ P<0.05）。上述数据表明，SP7可改善LRP5条件性缺失所致小鼠骨质疏松的骨缺损愈合过程。该研究为改善LRP5缺失所致骨质疏松提供了潜在治疗策略。