title: Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice.
abstract: Receptor activator of NF-κB ligand (RANKL) plays a key role in osteoclast-induced bone resorption across a range of degenerative bone diseases, and its specific inhibition has been recently approved as a treatment for women with postmenopausal osteoporosis at high or increased risk of fracture in the United States and globally. In the present study, we generated transgenic mice (TghuRANKL) carrying the human RANKL (huRANKL) genomic region and achieved a physiologically relevant pattern of RANKL overexpression in order to establish novel genetic models for assessing skeletal and extraskeletal pathologies associated with excessive RANKL and for testing clinical therapeutic candidates that inhibit human RANKL. TghuRANKL mice of both sexes developed early-onset bone loss, and the levels of huRANKL expression were correlated with bone resorption and disease severity. Low copy Tg5516 mice expressing huRANKL at low levels displayed a mild osteoporotic phenotype as shown by trabecular bone loss and reduced biomechanical properties. Notably, overexpression of huRANKL, in the medium copy Tg5519 line, resulted in severe early-onset osteoporosis characterized by lack of trabecular bone, destruction of the growth plate, increased osteoclastogenesis, bone marrow adiposity, increased bone remodeling, and severe cortical bone porosity accompanied by decreased bone strength. An even more severe skeletal phenotype developed in the high copy Tg5520 founder with extensive soft tissue calcification. Model validation was further established by evidence that denosumab, an antibody that inhibits human but not murine RANKL, fully corrected the hyper-resorptive and osteoporotic phenotypes of Tg5519 mice. Furthermore, overexpression of huRANKL rescued osteopetrotic phenotypes of RANKL-defective mice. These novel huRANKL transgenic models of osteoporosis represent an important advance for understanding the pathogenesis and treatment of high-turnover bone diseases and other disease states caused by excessive RANKL.
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece; Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Vagelis
authors.initials: V
authors.lastname: Rinotas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Niti
authors.forename: Romain
authors.initials: R
authors.lastname: Dacquin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonnet
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Chun-Ya
authors.initials: CY
authors.lastname: Han
authors.forename: Paul
authors.initials: P
authors.lastname: Kostenuik
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Serge
authors.initials: S
authors.lastname: Ferrari
authors.forename: Eleni
authors.initials: E
authors.lastname: Douni
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D010010:Osteoclasts / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053245:RANK Ligand; C505688:TNFSF11 protein, human
keywords: ANIMAL MODELS; BONE; OSTEOPOROSIS; RANKL; TREATMENT