LRP5-Mediated Lipid Uptake Modulates Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells.

Jiachen Lin,Ling Leng,Jieying Liu,Guihua Yang,Hai Wang,Guixing Qiu,Zhihong Wu,Zhifa Zheng

doi:10.3389/fcell.2021.766815

Abstract

Nutritional microenvironment determines the specification of progenitor cells, and lipid availability was found to modulate osteogenesis in skeletal progenitors. Here, we investigated the implications of lipid scarcity in the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) and the role of low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor transducing canonical Wnt/beta-catenin signals, in BMSC lipid uptake during osteogenesis. The osteogenic differentiation of murine BMSCs was suppressed by lipid scarcity and partially rescued by additional fatty acid treatment with oleate. The enhancement of osteogenesis by oleate was found to be dosage-dependent, along with the enhanced activation of beta-catenin and Wnt target genes. Conditional knockout (CKO) of Lrp5 gene in murine mesenchymal lineage using Lrp5fl/fl;Prrx1-cre mice led to decreased bone quality and altered fat distribution in vivo. After Lrp5 ablation using adenoviral Cre-recombinase, the accumulation of lipid droplets in BMSC cytoplasm was significantly reduced, and the osteogenesis of BMSCs was suppressed. Moreover, the impaired osteogenesis due to either lipid scarcity or Lrp5 ablation could be rescued by recombinant Wnt3a protein, indicating that the osteogenesis induced by Wnt/beta-catenin signaling was independent of LRP5-mediated lipid uptake. In conclusion, lipid scarcity suppresses BMSC osteogenic differentiation. LRP5 plays a role in the uptake of lipids in BMSCs and therefore mediates osteogenic specification.

Highlights

Nutritional microenvironment determines the specification of skeletal progenitor cells
alkaline phosphatase (ALP) staining was performed on days 5, 7, and 11 after osteogenic induction, and ALP activity was measured to determine the osteogenesis in different mediums (Figures 1A,B)
In light of the fact that Wnt-lipoprotein receptor-related protein 5 (LRP5) signaling was found to participate in the lipid metabolism and bone formation in skeletal progenitors, we examined whether this modulation is regulated by lipid availability or not

Summary

Introduction

Nutritional microenvironment determines the specification of skeletal progenitor cells. Wnt-LRP5 Regulation in BMSC Osteogenesis and regeneration after bone fracture (van Gastel et al, 2020). Low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) is a member of LDL receptor family and known as a co-receptor for canonical Wnt/beta-catenin signaling pathway and transduces key molecular signals in bone development and homeostasis (Cui et al, 2011; Baron and Kneissel, 2013; Kobayashi et al, 2016). Several newly uncovered molecular mechanisms about Wnt-independent LRP5 modulation in bone (Clement-Lacroix et al, 2005; Yadav and Ducy, 2010; Chin et al, 2015; Frey et al, 2015; He et al, 2020) suggested a more complicated role of LRP5 in skeletal progenitors. There are other studies indicating the modulatory role of LRP5 in lipid metabolism (Magoori et al, 2003; Loh et al, 2015)

Methods

Results

Conclusion