title: Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model.
abstract: Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl) under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543 NUS Centre for Bioimaging Sciences (CBIS), Singapore 117557, Singapore.
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Paul Eckhard
authors.initials: PE
authors.lastname: Witten
authors.affiliation: Department of Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Huysseune
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543 NUS Centre for Bioimaging Sciences (CBIS), Singapore 117557, Singapore.
authors.forename: Anita
authors.initials: A
authors.lastname: Buettner
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543 NUS Centre for Bioimaging Sciences (CBIS), Singapore 117557, Singapore.
authors.forename: Thuy Thanh
authors.initials: TT
authors.lastname: To
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543 NUS Centre for Bioimaging Sciences (CBIS), Singapore 117557, Singapore dbswcw@nus.edu.sg.
authors.forename: Christoph
authors.initials: C
authors.lastname: Winkler
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D009990:Oryzias; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D010024:Osteoporosis / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D004164:Diphosphonates; D053245:RANK Ligand
keywords: Bone modeling; Homeostasis; Medaka; Osteoblast-osteoclast coupling; Osteoporosis; Remodeling