Wnt10b is required for the increase in cancellous bone caused by oxidized phospholipids blockade

Oxidized phospholipids containing phosphatidylcholine (PC-OxPLs), present on oxidized low-density lipoproteins (OxLDL) and apoptotic cells, are pathogenic in osteoporosis. PC-OxPLs are bound by the IgM E06 antibody, which blocks their deleterious effects. Overexpression of the antigen-binding domain of E06 (E06-scFv) increases bone mass in 6-month-old mice and attenuates high fat diet- and age-induced bone loss by increasing osteoblast number and function. The mechanisms mediating the anabolic effect of oxidized phospholipids blockade are unclear. In previous work, we showed that E06-scFv upregulates the expression of Wnt10b and Wnt signaling in vivo. We report herein that the bulk of Wnt10b in the bone microenvironment originates from osteoblast lineage cells. OxLDL decreases the expression of Wnt10b and Wnt target genes in osteoblastic cells, and single cell RNA-sequencing (scRNA-seq) of mesenchymal cells reveals an increase in Wnt10b and Wnt target genes in pre-osteoblasts and osteoblasts of E06-scFv transgenic mice compared to WT. Loss of Wnt10b prevents the increases in BMD by DXA and in vertebral and femoral cancellous bone in 6-month-old E06-scFv transgenic male mice, and attenuates these increases in female mice. Collectively, these findings indicate that oxidized phospholipids decrease bone mass, at least in part, by suppressing Wnt10b.