LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation.

The Wnt/β-catenin signaling pathway plays a pivotal role in regulating osteoblast differentiation and bone formation. Here, we identify low-density lipoprotein (LDL) receptor-related protein 8 (LRP8) as a positive regulator of Wnt/β-catenin signaling. In a small interfering RNA (siRNA) screen, LRP8 was shown to be required for Wnt/β-catenin-induced transcriptional reporter activity. We found that ectopic expression of LRP8 increased Wnt-induced transcriptional responses, and promoted Wnt-induced β-catenin accumulation. Moreover, knockdown of LRP8 resulted in a decrease in β-catenin levels and suppression of Wnt/β-catenin-induced Axin2 transcription. Functional studies in KS483 osteoprogenitor cells showed that LRP8 depletion resulted in impaired activation of endogenous Wnt-induced genes and decreased osteoblast differentiation and mineralization, whereas LRP8 ectopic expression had the opposite effect. These results identify LRP8 as a novel positive factor of canonical Wnt signaling pathway and show its involvement in Wnt-induced osteoblast differentiation.