ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2014
Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 72 citations in OpenAlex.
- Identification of candidate receptors mediating the osteoanabolic influence of Wnt1.JBMR plus · 2026Article
- ESWT attenuates compressive stress-induced cartilaginous endplate degeneration via modulation of theFrontiers in bioengineering and biotechnology · 2026Article
- Modified criteria for identifying elevated bone mass.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2025Article
- Role of SOST in Response to Mechanical Stimulation in Bone and Extraosseous Organs.Biomolecules · 2025Review
- Activation of Wnt signaling in human fracture callus and nonunion tissues.Bone reports · 2024Article
- Potential Targeting Mechanisms for Bone-Directed Therapies.International journal of molecular sciences · 2024Review
- Research Progress on the Mechanism of the SFRP-Mediated Wnt Signalling Pathway Involved in Bone Metabolism in Osteoporosis.Molecular biotechnology · 2024Review
- Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases.Journal of anatomy · 2023Article
- Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 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
- Osteocytes regulate bone anabolic response to mechanical loading in male mice via activation of integrin α5.Bone research · 2022Article
- Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Article
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- The Pathophysiology of Osteoporosis after Spinal Cord Injury.International journal of molecular sciences · 2021Review
- The effect of strontium ranelate on titanium particle-induced periprosthetic osteolysis regulated by WNT/β-catenin signaling in vivo and in vitro.Bioscience reports · 2021Article
- Synergistic Effects of Erzhi Pill Combined With Methotrexate on Osteoblasts MediatedFrontiers in pharmacology · 2020Article
- Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.American journal of human genetics · 2019Article
- Expression of Sclerostin in Osteoporotic Fracture Patients Is Associated with DNA Methylation in the CpG Island of theInternational journal of genomics · 2019Article
- Strontium ranelate inhibits wear particle-induced aseptic loosening in mice.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2018Article
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Authors and funding
10 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The bone formation inhibitor sclerostin encoded by SOST binds in vitro to low-density lipoprotein receptor-related protein (LRP) 5/6 Wnt co-receptors, thereby inhibiting Wnt/β-catenin signaling, a central pathway of skeletal homeostasis. Lrp5/LRP5 deficiency results in osteoporosis-pseudoglioma (OPPG), whereas Sost/SOST deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking Sost (Sost(-/-) ), Lrp5 (Lrp5(-/-) ), or both (Sost(-/-) ;Lrp5(-/-) ) to elucidate the mechanism of action of Sost in vivo. Sost deficiency-induced bone gain was significantly blunted in Sost(-/-) ;Lrp5(-/-) mice. Yet the Lrp5 OPPG phenotype was fully rescued in Sost(-/-) ;Lrp5(-/-) mice and most bone parameters were elevated relative to wild-type. To test whether the remaining bone increases in Sost(-/-) ;Lrp5(-/-) animals depend on Lrp6, we treated wild-type, Sost(-/-) , and Sost(-/-) ;Lrp5(-/-) mice with distinct Lrp6 function blocking antibodies. Selective blockage of Wnt1 class-mediated Lrp6 signaling reduced cancellous bone mass and density in wild-type mice. Surprisingly, it reversed the abnormal bone gain in Sost(-/-) and Sost(-/-) ;Lrp5(-/-) mice to wild-type levels irrespective of enhancement or blockage of Wnt3a class-mediated Lrp6 activity. Thus, whereas Sost deficiency-induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class-induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from LRP5 loss-of-function should benefit from principles antagonizing SOST/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to SOST deficiency, such as sclerosteosis, van Buchem disease, and autosomal dominant craniodiaphyseal dysplasia, which are rare disorders without viable treatment options.
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