149856 20251017144608.0 doi 10.1074/jbc.M110.190330 sideral 124410 ART-2011-124410 eng Leupin, Olivier Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function 2011 Access copy available to the general public Unrestricted Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. lthough it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the inderlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/-catenin signaling. We found the extracellular -propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone. info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 4.773 2011 BIOCHEMISTRY & MOLECULAR BIOLOGY 66 / 287 = 0.23 2011 Q1 T1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Piters, Elke Halleux, Christine Hu, Shouih Kramer, Ina Morvan, Frederic Bouwmeester, Tewis Schirle, Markus Bueno-Lozano, Manuel Universidad de Zaragoza (orcid)0000-0002-6166-3612 Ramos, Feliciano Universidad de Zaragoza (orcid)0000-0002-5732-2209 Itin, Peter Boudin, Eveline Freitas, Fenna Jennes, Karen Brannetti, Barbara Charara, Nadine Ebersbach, Hilmar Geisse, Sabine Lu, Chris Kneissel, Michaela 1006 255 Universidad de Zaragoza Dpto. Fisiatría y Enfermería Área Enfermería 1010 670 Universidad de Zaragoza Dpto. Pediatría Radiol.Med.Fís Área Pediatría 286, 22 (2011), 19489-19500 J. biol. chem. Journal of Biological Chemistry 0021-9258 1738158 http://zaguan.unizar.es/record/149856/files/texto_completo.pdf Versión publicada 3896104 http://zaguan.unizar.es/record/149856/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:149856 articulos driver 2025-10-17-14:16:04 ARTICLE