ArticleProceedings of the National Academy of Sciences of the United States of America2014
Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 121 citations in OpenAlex.
- Blocking interaction of sclerostin loop3 with osteoblastic LRP4 counteracts bone loss without increasing arterial stiffness during mechanical unloading.Journal of orthopaedic translation · 2026Article
- Sclerostin deficiency sensitizes white adipocytes to thermogenic signals that induce beiging in mice.Nature communications · 2026Article
- Relationship between bone resorption and sclerostin regulation in apical periodontitis lesions.Odontology · 2026Article
- Bone and muscle crosstalk in ageing and disease.Nature reviews. Endocrinology · 2025Review
- Mapping the sclerostin-LRP4 binding interface identifies critical interaction hotspots in loops 1 and 3 of sclerostin.FEBS letters · 2025Article
- The Relationship between Sclerostin and Kidney Transplantation Mineral Bone Disorders: A Molecule of Controversies.Calcified tissue international · 2024Review
- Effect of α7 nAChR-autophagy axis of deciduous tooth pulp stem cells in regulating IL-1β in the process of physiological root resorption of deciduous teeth.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Induction of osteoblast apoptosis stimulates macrophage efferocytosis and paradoxical bone formation.Bone research · 2024Article
- Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease.Bone research · 2024Review
- Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives.Journal of orthopaedic translation · 2024Review
- Severe Osteoporosis With PathogenicJCEM case reports · 2024Article
- An Additional Lrp4 High Bone Mass Mutation Mitigates the Sost-Knockout Phenotype in Mice by Increasing Bone Remodeling.Calcified tissue international · 2024Article
- A framework for defining mesenchymal cell types associated with murine periosteal and endosteal bone.bioRxiv : the preprint server for biology · 2023Article
- Wnt signaling: Essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders.Genes & diseases · 2023Review
- A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss.Bone research · 2023Article
- Polymorphism of LRP4 Gene (rs9667108) among Post Menopause Women with Osteoporosis.Iranian journal of public health · 2023Article
- LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low-Density Lipoprotein Receptor-Related Protein 6.JBMR plus · 2023Article
- Endocrine Functions of Sclerostin.Current opinion in endocrine and metabolic research · 2023Article
- Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study.Frontiers in genetics · 2023Article
- Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Wingless-type) 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.