title: LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Maarten
authors.initials: M
authors.lastname: van Dinther
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D055550:Protein Stability; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D026502:LDL-Receptor Related Proteins; D060509:Wnt3A Protein; D051176:beta Catenin; C098773:low density lipoprotein receptor-related protein 8