000149856 001__ 149856
000149856 005__ 20251017144608.0
000149856 0247_ $$2doi$$a10.1074/jbc.M110.190330
000149856 0248_ $$2sideral$$a124410
000149856 037__ $$aART-2011-124410
000149856 041__ $$aeng
000149856 100__ $$aLeupin, Olivier
000149856 245__ $$aBone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function
000149856 260__ $$c2011
000149856 5060_ $$aAccess copy available to the general public$$fUnrestricted
000149856 5203_ $$aHumans 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.
000149856 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000149856 590__ $$a4.773$$b2011
000149856 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b66 / 287 = 0.23$$c2011$$dQ1$$eT1
000149856 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000149856 700__ $$aPiters, Elke
000149856 700__ $$aHalleux, Christine
000149856 700__ $$aHu, Shouih
000149856 700__ $$aKramer, Ina
000149856 700__ $$aMorvan, Frederic
000149856 700__ $$aBouwmeester, Tewis
000149856 700__ $$aSchirle, Markus
000149856 700__ $$0(orcid)0000-0002-6166-3612$$aBueno-Lozano, Manuel$$uUniversidad de Zaragoza
000149856 700__ $$0(orcid)0000-0002-5732-2209$$aRamos, Feliciano$$uUniversidad de Zaragoza
000149856 700__ $$aItin, Peter
000149856 700__ $$aBoudin, Eveline
000149856 700__ $$aFreitas, Fenna
000149856 700__ $$aJennes, Karen
000149856 700__ $$aBrannetti, Barbara
000149856 700__ $$aCharara, Nadine
000149856 700__ $$aEbersbach, Hilmar
000149856 700__ $$aGeisse, Sabine
000149856 700__ $$aLu, Chris
000149856 700__ $$aKneissel, Michaela
000149856 7102_ $$11006$$2255$$aUniversidad de Zaragoza$$bDpto. Fisiatría y Enfermería$$cÁrea Enfermería
000149856 7102_ $$11010$$2670$$aUniversidad de Zaragoza$$bDpto. Pediatría Radiol.Med.Fís$$cÁrea Pediatría
000149856 773__ $$g286, 22 (2011), 19489-19500$$pJ. biol. chem.$$tJournal of Biological Chemistry$$x0021-9258
000149856 8564_ $$s1738158$$uhttps://zaguan.unizar.es/record/149856/files/texto_completo.pdf$$yVersión publicada
000149856 8564_ $$s3896104$$uhttps://zaguan.unizar.es/record/149856/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000149856 909CO $$ooai:zaguan.unizar.es:149856$$particulos$$pdriver
000149856 951__ $$a2025-10-17-14:16:04
000149856 980__ $$aARTICLE