title: Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis.
abstract: Osteoclast differentiation factor, ODF, also called RANKL, TRANCE, or OPGL, is a key molecule for osteoclast differentiation and activation, and is thought to act as a membrane-associated molecule in bone remodeling. Recent study suggested that soluble ODF (sODF) released from T cells also has some roles in bone resorption. To investigate the physiological and pathological function of sODF, we generated two types of transgenic mice overexpressing sODF. Mice overexpressing sODF ubiquitously from the early developmental stage died at the late fetal stage. The other type of mice, expressing sODF only in the liver after birth, grew to maturity with normal body size and weight. However, they exhibited a marked decrease in bone mineral density with aging compared with their non-transgenic littermates, and in addition, the strength of their femurs was extremely reduced. Histological analysis showed that the trabecular bone mass was decreased at 6 weeks of age and was sparse at age 3-4 months. The number of osteoclasts was significantly increased, while the number of osteoblasts was not altered on the surface of young trabecular bone. These results indicate that excessive production of sODF causes osteoporosis by accelerated osteoclastogenesis. The transgenic mouse overexpressing sODF in the liver could serve as a useful animal model for studying bone remodeling and evaluating therapeutic agents for osteoporosis.
authors.affiliation: Research Institute of Life Science, Snow Brand Milk Products, Co., Ltd., Tochigi, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Mizuno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Masaki
authors.initials: M
authors.lastname: Hoshi
authors.forename: Osamu
authors.initials: O
authors.lastname: Shibata
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yano
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Fujise
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kinosaki
authors.forename: Kyoji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Eisuke
authors.initials: E
authors.lastname: Tsuda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Murakami
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Kanji
authors.initials: K
authors.lastname: Higashio
mesh_terms: D000208:Acute Disease; D000818:Animals; D001835:Body Weight; D015519:Bone Density; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005313:Fetal Death; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D012995:Solubility
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse