ArticleScience translational medicine2013
Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome.
Article in Science translational medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 78 citations in OpenAlex.
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- Incident Vertebral Fractures During Romosozumab Treatment in a Patient With a PathogenicJCEM case reports · 2025Article
- Affinity targeting of therapeutic proteins to the bone surface-local delivery of sclerostin-neutralizing antibody enhances efficacy.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Article
- Severe Osteoporosis With PathogenicJCEM case reports · 2024Article
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- Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis.Nature communications · 2023Article
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- Single cell cortical bone transcriptomics define novel osteolineage gene sets altered in chronic kidney disease.Frontiers in endocrinology · 2023Article
- Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Notum Deletion From Late-Stage Skeletal Cells Increases Cortical Bone Formation and Potentiates Skeletal Effects of Sclerostin Inhibition.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2021Article
- Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.International journal of molecular sciences · 2021Article
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- Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting.JBMR plus · 2021Article
- Osteoporosis Treatment with Anti-Sclerostin Antibodies-Mechanisms of Action and Clinical Application.Journal of clinical medicine · 2021Review
- Generation and Characterization of Mouse Models for Skeletal Disease.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Rheumatoid Arthritis in the View of Osteoimmunology.Biomolecules · 2020Review
- Single-Cell RNA Sequencing of Calvarial and Long-Bone Endocortical Cells.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2020Article
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10 authors at 7 institutions in 1 country.
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Abstract
Osteoporosis pseudoglioma syndrome (OPPG) is a rare genetic disease that produces debilitating effects in the skeleton. OPPG is caused by mutations in LRP5, a WNT co-receptor that mediates osteoblast activity. WNT signaling through LRP5, and also through the closely related receptor LRP6, is inhibited by the protein sclerostin (SOST). It is unclear whether OPPG patients might benefit from the anabolic action of sclerostin neutralization therapy (an approach currently being pursued in clinical trials for postmenopausal osteoporosis) in light of their LRP5 deficiency and consequent osteoblast impairment. To assess whether loss of sclerostin is anabolic in OPPG, we measured bone properties in a mouse model of OPPG (Lrp5(-/-)), a mouse model of sclerosteosis (Sost(-/-)), and in mice with both genes knocked out (Lrp5(-/-);Sost(-/-)). Lrp5(-/-);Sost(-/-) mice have larger, denser, and stronger bones than do Lrp5(-/-) mice, indicating that SOST deficiency can improve bone properties via pathways that do not require LRP5. Next, we determined whether the anabolic effects of sclerostin depletion in Lrp5(-/-) mice are retained in adult mice by treating 17-week-old Lrp5(-/-) mice with a sclerostin antibody for 3 weeks. Lrp5(+/+) and Lrp5(-/-) mice each exhibited osteoanabolic responses to antibody therapy, as indicated by increased bone mineral density, content, and formation rates. Collectively, our data show that inhibiting sclerostin can improve bone mass whether LRP5 is present or not. In the absence of LRP5, the anabolic effects of SOST depletion can occur via other receptors (such as LRP4/6). Regardless of the mechanism, our results suggest that humans with OPPG might benefit from sclerostin neutralization therapies.
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