title: An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts.
abstract: Sclerostin is an important regulator of bone homeostasis and canonical Wnt signaling is a key regulator of osteogenesis. Strontium ranelate is a treatment for osteoporosis that has been shown to reduce fracture risk, in part, by increasing bone formation. Here we show that exposure of human osteoblasts in primary culture to strontium increased mineralization and decreased the expression of sclerostin, an osteocyte-specific secreted protein that acts as a negative regulator of bone formation by inhibiting canonical Wnt signaling. Strontium also activated, in an apparently separate process, an Akt-dependent signaling cascade via the calcium-sensing receptor that promoted the nuclear translocation of β-catenin. We propose that two discrete pathways linked to canonical Wnt signaling contribute to strontium-induced osteogenic effects in osteoblasts.
authors.affiliation: Department of Physiology and Bosch Institute, University of Sydney, New South Wales, 2006, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Rybchyn
authors.forename: Michael
authors.initials: M
authors.lastname: Slater
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Conigrave
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Mason
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D009942:Organometallic Compounds; C422903:SOST protein, human; D013876:Thiophenes; D051153:Wnt Proteins; D051176:beta Catenin; C081587:strontium ranelate; D051057:Proto-Oncogene Proteins c-akt