ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2014
Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta.
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 49 papers.
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49 citing papers in PubMed, 82 citations in OpenAlex.
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- Targeting strategies for bone diseases: signaling pathways and clinical studies.Signal transduction and targeted therapy · 2023Review
- Murine Animal Models in Osteogenesis Imperfecta: The Quest for Improving the Quality of Life.International journal of molecular sciences · 2022Review
- Drug discovery of sclerostin inhibitors.Acta pharmaceutica Sinica. B · 2022Review
- Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types.Endocrine reviews · 2022Review
- Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.Theranostics · 2022Article
- Improving Bone Health by Optimizing the Anabolic Action of Wnt Inhibitor Multitargeting.JBMR plus · 2021Article
- Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2021Article
- Gender-Related Impact of Sclerostin Antibody on Bone in the Osteogenesis Imperfecta Mouse.Frontiers in genetics · 2021Article
- Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta.PloS one · 2021Article
- Engraftment of skeletal progenitor cells by bone-directed transplantation improves osteogenesis imperfecta murine bone phenotype.Stem cells (Dayton, Ohio) · 2020Article
- Combination therapy in the Col1a2Bone · 2020Article
- Transcriptome profile of highly osteoblastic/cementoblastic periodontal ligament cell clones.Journal of applied oral science : revista FOB · 2020Article
- Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
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Abstract
The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI.
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