SP7 transcription factor ameliorates bone defect healing in low-density lipoprotein receptor-related protein 5 (LRP5)-dependent osteoporosis mice

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 <i>LRP5</i> 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 <i>LRP5</i> 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 (<i>ALP</i>), Runt-related transcription factor 2 (<i>Runx2</i>), and <i>β‍-catenin</i> (<i>P</i><0.05). For the in vivo experiment, the SP7 overexpression virus was injected into a bone defect model of <i>LRP5</i> cKO mice, resulting in increased bone mineral density (BMD) (<i>P</i><0.001) and volumetric density (bone volume (BV)/total volume (TV)) (<i>P</i><0.001), and decreased trabecular separation (Tb.‍Sp) (<i>P</i><0.05). These data suggested that SP7 could ameliorate bone defect healing in <i>LRP5</i> cKO mice. Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.