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Bone overgrowth-associated mutations in LRP4 impair sclerostin-facilitator function.

Leupin, Olivier and Piters, Elke and Halleux, Christine and Hu, Shouih and Kramer, Ina and Morvan, Frederic and Bouwmeester, Tewis and Schirle, Markus and Bueno-Lozano, Manuel and Ramos Fuentes, Feliciano J and Itin, Peter H and Boudin, Eveline and De Freitas, Fenna and Jennes, Karen and Brannetti, Barbara and Charara, Nadine and Ebersbach, Hilmar and Geisse, Sabine and Lu, Chris X and Bauer, Andreas and Van Hul, Wim and Kneissel, Michaela (2011) Bone overgrowth-associated mutations in LRP4 impair sclerostin-facilitator function. The Journal of biological chemistry. ISSN 1083-351X

Abstract

Abstract
Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. While it is well established that sclerostin is an osteocyte secreted bone formation inhibitor, the underlying 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/beta-catenin signaling. We found the extracellular beta-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 lentiviral-mediated shRNA delivery blocked sclerostin-inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W, 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 sclerostin inhibitory function on bone formation, thus identifying a novel role for LRP4 in bone.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4868

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