Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors

Holdsworth, Gill; Slocombe, Patrick M.; Doyle, Carl; Sweeney, Bernadette; Veverka, Václav; Riche, Kelly Le; Franklin, Richard J.; Compson, Joanne E.; Brookings, Daniel C.; Turner, James M. A.; Kennedy, Jeffery; Garlish, Rachael; Shi, Jiye; Newnham, Laura E; McMillan, David; Muzylak, M; Carr, Mark D.; Henry, Alistair J.; Ceska, T.A.; Robinson, Martyn K.

doi:10.1074/jbc.m112.350108

Cited by 84 publications

(99 citation statements)

References 45 publications

(53 reference statements)

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“…30 The Wnt3a class encompasses Wnt3 and 3a and binds b-propeller 3 of LRP5/6. 30 Interestingly, sclerostin has been shown to inhibit the Wnt1 class by binding to the first b-propeller region of LRP5/6 but not the Wnt3a class, 24,30,31 which is coherent with our result. The fact that sclerostin could inhibit BMP2-or Wnt3a-induced osteoblast differentiation without antagonizing their respective canonical signaling suggested that it could function through another signaling pathway.…”

Section: Discussionsupporting

confidence: 91%

Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/β-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro

Thouverey¹,

Caverzasio²

2015

BoneKEy Reports

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Sclerostin inhibits bone formation mostly by antagonizing LRP5/6, thus inhibiting Wnt signaling. However, experiments with genetically modified mouse models suggest that a significant part of sclerostin-mediated inhibition of bone formation is due to interactions with other binding partners. The objective of the present work was to identify signaling pathways affected by sclerostin in relation with its inhibitory action on osteogenic differentiation of C3H10T1/2 cells, MC3T3-E1 cells and primary osteoblasts. Sclerostin inhibited BMP2-induced osteoblast differentiation without altering SMAD1/5 phosphorylation and transcriptional activity. Moreover, sclerostin prevented Wnt3a-mediated osteoblastogenesis without affecting LRP5/6 phosphorylation or b-catenin transcriptional activity. In addition, sclerostin inhibited mineralization promoted by GSK3 inhibition, which mimics canonical Wnt signaling without activation of LRP5/6, suggesting that sclerostin can prevent osteoblast differentiation without antagonizing LRP5/6. Finally, we found that sclerostin could activate platelet-derived growth factor receptor (PDGFR) and its downstream signaling pathways PLCc, PKC, Akt and ERK1/2. PDGFR inhibition could reverse sclerostin-mediated inhibitory activity on BMP2-induced osteoblast differentiation. Therefore, our data suggest that sclerostin can activate PDGFR signaling by itself, and this functional interaction may be involved in the negative effect of sclerostin on osteoblast differentiation.

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Section: Discussionsupporting

confidence: 91%

Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/β-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro

Thouverey¹,

Caverzasio²

2015

BoneKEy Reports

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“…Its role in negatively regulating bone mass is exemplified by naturally occurring SOST loss-of-function mutations in humans, which cause the severe bone overgrowth disorders sclerosteosis [Mendelian Inheritance in Man (MIM269500)] (3,4), van Buchem disease (VBD) (MIM) 239100 (3,5,6), and craniodiaphyseal dysplasia (CDD) (MIM 122860) (7). Sclerostin inhibits WNT/β-catenin signaling, considered as canonical WNT signaling by binding to WNT coreceptors LRP5 and LRP6 (8)(9)(10)(11)(12)(13)(14)(15), thereby disrupting the formation of a WNT1-type ligandreceptor complex (9,11,12). In addition, we recently identified a facilitator of sclerostin action, the low-density lipoprotein receptor-related protein (LRP) family member LRP4.…”

mentioning

confidence: 99%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Winglesstype) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.LRP4 | SOST | sclerostin | WNT | bone anabolism

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“…For the C-terminal part of Dkk1 the binding to ␤ -propeller III involves similar residues, except the residues corresponding to Asn(1082), as if binding an NxI motif, although no NxI motif was seen in this part of Dkk1 ( 10,11 ). Furthermore, it has been elegantly demonstrated by Holdsworth et al that sclerostin also binds its cognate receptors LRP5 and LRP6 via its NxI motif ( 64 ). Moreover, as LRP2 contains three ␤ -propellers with an SBiN motif, it is interesting that an analysis of the sequences of known LRP2 ligands reveals that cubilin, vitamin D-binding protein, transcobalmin-vitamin B12, serum albumin, and apoB all contain one or two copies of exposed NxI motifs, although LRP2 binding using this motif has not yet been shown.…”

Section: Biological Implications Of Protein Interactions Of the Lrp ␤mentioning

confidence: 98%

New horizons for lipoprotein receptors: communication by β-propellers

Andersen

Dagil

Kragelund

2013

Journal of Lipid Research

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sorLA/LR11], the LARGE receptors [low-density lipoprotein receptor-like protein 4, 5, and 6 (LRP4, LRP5, and LRP6)] and the GIANT receptors {low-density lipoprotein receptor-like protein 1, protein 1B, and protein 2 [LRP1, LRP1B, and LRP2 (also known as megalin)]} ( Fig. 1A ). Unrelated to size, the LRs are all modularly constructed from a limited subset of three different domains: the complement type repeat (CR)-domains, the epidermal growth factor (EGF)-like domains, and the ␤ -propellers containing YWTDrepeats (YWTD ␤ -propeller). The related members contain additional structural entities, such as fi bronectin type III (FNIII) domains, vacuolar protein sorting 10 (VPS10) homology domains, and G-domains ( 2, 3 ). Despite this apparent structural simplicity, only few structures have been solved, and the foundation for an explication of their structure-function relations is far from complete.Very early, around the 1980s ( 4 ), it was established that ligand binding to LRs involved the small ( ‫ف‬ 40 residues) CR-domains (also termed receptor class A repeats), which are omnipresent in the family, Fig. 1B . These domains are clustered modularly in disulphide-bonded and Ca 2+ -stabilized regions, and for more than two decades, they have been seen as the sole ligand interaction regions in LRs. In contrast, the ␤ -propellers and the EGF-like domains have merely been seen as spacer regions ensuring a proper distance between clusters of CR-domain binding sites aiding optimized adaptation in ligand binding ( 5 ). In 1998, an analysis of the YWTD-repeat sequences of LRs suggested that each region folds into a ␤ -propeller containing six blades ( 1 ), and in 2001, this was confi rmed by the crystal structure of this region of LDLR ( 6 ). Shortly after, the structure of nidogen-1 followed ( 7 ), showing that Abstract The lipoprotein receptor (LR) family constitutes a large group of structurally closely related receptors with broad ligand-binding specifi city. Traditionally, ligand binding to LRs has been anticipated to involve merely the complement type repeat (CR)-domains omnipresent in the family. Recently, this dogma has transformed with the observation that ␤ -propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the ␤ -propellers as binding targets depends on receptor subgroups. In particular, we highlight the shutter mechanism of ␤ -propellers as a general recognition motif for NxI-containing ligands, and we present indications that the generalized ␤ -propeller-induced ligand release mechanism is not applicable for the larger LRs. For the giant LR members, we present evidence that their ␤ -propellers may also actively engage in ligand binding. We therefore advocate for an increased focus on solving the structure-function relationship of this group of important biological receptors. The family of proteins containing Tyr-Trp-Thr-Asp (YWTD)-repeat ␤ -propellers constitutes a group of structurally related gl...

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Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors

Cited by 84 publications

References 45 publications

Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/β-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro

Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/β-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

New horizons for lipoprotein receptors: communication by β-propellers

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