Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice

dc.contributor.author	Rinotas, V	en
dc.contributor.author	Niti, A	en
dc.contributor.author	Dacquin, R	en
dc.contributor.author	Bonnet, N	en
dc.contributor.author	Stolina, M	en
dc.contributor.author	Han, C-Y	en
dc.contributor.author	Kostenuik, P	en
dc.contributor.author	Jurdic, P	en
dc.contributor.author	Ferrari, S	en
dc.contributor.author	Douni, E	en
dc.date.accessioned	2014-06-06T06:53:06Z
dc.date.available	2014-06-06T06:53:06Z
dc.date.issued	2014	en
dc.identifier.issn	15234681	en
dc.identifier.uri	http://dx.doi.org/10.1002/jbmr.2112	en
dc.identifier.uri	http://62.217.125.90/xmlui/handle/123456789/6362
dc.subject	animal models	en
dc.subject	bone	en
dc.subject	osteoporosis	en
dc.subject	RANKL	en
dc.subject	treatment	en
dc.subject.other	denosumab	en
dc.subject.other	Albers Schoenberg disease	en
dc.subject.other	animal experiment	en
dc.subject.other	animal model	en
dc.subject.other	article	en
dc.subject.other	biomechanics	en
dc.subject.other	bone remodeling	en
dc.subject.other	bone strength	en
dc.subject.other	controlled study	en
dc.subject.other	disease severity	en
dc.subject.other	female	en
dc.subject.other	gene	en
dc.subject.other	gene dosage	en
dc.subject.other	gene overexpression	en
dc.subject.other	genetic model	en
dc.subject.other	male	en
dc.subject.other	mouse	en
dc.subject.other	nonhuman	en
dc.subject.other	osteolysis	en
dc.subject.other	osteoporosis	en
dc.subject.other	phenotype	en
dc.subject.other	porosity	en
dc.subject.other	protein analysis	en
dc.subject.other	receptor activator of nuclear factor kappa B gene	en
dc.subject.other	soft tissue calcification	en
dc.subject.other	trabecular bone	en
dc.subject.other	transgenic mouse	en
dc.title	Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice	en
heal.type	journalArticle	en
heal.identifier.primary	10.1002/jbmr.2112	en
heal.publicationDate	2014	en
heal.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. © 2014 American Society for Bone and Mineral Research.	en
heal.publisher	Wiley-Blackwell	en
heal.journalName	Journal of Bone and Mineral Research	en
dc.identifier.issue	5	en
dc.identifier.volume	29	en
dc.identifier.doi	10.1002/jbmr.2112	en
dc.identifier.spage	1158	en
dc.identifier.epage	1169	en