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

Chang, Ming-Kang; Krämer, Ina; Huber, Thomas; Kinzel, Bernd; Guth‐Gundel, Sabine; Leupin, Olivier; Kneissel, Michaela

doi:10.1073/pnas.1413828111

Cited by 108 publications

(99 citation statements)

References 58 publications

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“…Since the submission of our paper, Chang et al report that ablation of Lrp4 in OB increases bone formation and bone mass and elevates serum sclerostin levels (33).…”

Section: Methodsmentioning

confidence: 81%

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

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

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Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bonemass homeostasis.one remodeling is a dynamic process essential for maintenance of skeletal integrity and bone homeostasis (1). Bone mass is tightly regulated by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs). OBs are differentiated from bone marrow stromal cells (BMSCs) or mesenchymal progenitor cells, whereas OCs are derived from hematopoietic bone marrow macrophages or myeloid monocytes (BMMs). The balance of bone formation and resorption is critical for maintenance of healthy bone mass. The imbalance of bone formation and resorption could result in high-bone-mass disorders such as sclerosteosis and van Buchem disease or bone loss such as osteoporosis.The canonical Wnt/β-catenin signaling is critical to regulate bone-mass homeostasis (1, 2). Binding of Wnt ligands to a dualreceptor complex of frizzled and Lrp5/6 leads to accumulation of cytoplasmic β-catenin and translocation of β-catenin into the nucleus to regulate gene expression. This pathway is required for commitment of mesenchymal stem cells to the OB lineage, OB precursor cell proliferation and differentiation, and OC genesis and activation (1-3). Clinically, Lrp5 mutations are associated with the osteoporosis-pseudoglioma syndrome, a low-bone-mass disorder (4), as well as with high-bone-mass disorders (5, 6).Lrp4 is a member of LDL family protein, containing a large extracellular region with multiple LDLa, EGF-like, and β-propeller repeats, a transmembrane domain, and a short C-terminal region. Lrp4 is a receptor of agrin (7,8), critical for neuromuscular junction formation. Mice lacking Lrp4 (null allele) die at birth because of inability to breathe (9). Lrp4 is also highly related to...

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“…Since the submission of our paper, Chang et al report that ablation of Lrp4 in OB increases bone formation and bone mass and elevates serum sclerostin levels (33).…”

Section: Methodsmentioning

confidence: 81%

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

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

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“…In postnatal bone, loss of Lrp4 in osteoblasts leads to increased bone mass reminiscent of bone phenotypes observed in mice deficient for Sost (Chang et al, 2014a;Collette et al, 2012;Li et al, 2008;Xiong et al, 2015). Human patients with the LRP4 mutation R1170W display bone overgrowth and the mutation results in reduced binding to SOST and abolishes the LRP4 function as a facilitator of SOST in cultured cells (Leupin et al, 2011).…”

Section: Dissecting Domain-specific Roles For Lrp4mentioning

confidence: 99%

Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

et al. 2017

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During development and homeostasis, precise control of Wnt/β-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/β-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/β-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/β-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.

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“…2). SOST and LRP4 loss-offunction mutations cause increased bone mass, a finding that can be mimicked therapeutically for the treatment of osteoporosis by SOST or LRP4 neutralizing antibodies (16,17).…”

Section: Upstream Inhibitors Of Wnt Production and Functionmentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

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Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of b-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/b-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.

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

Cited by 108 publications

References 58 publications

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

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