title: Osteoprotegerin administration reduces femural bone loss in ovariectomized mice via impairment of osteoclast structure and function.
abstract: Osteoprotegerin (OPG) is a novel osteoblast-derived secreted member of the tumour necrosis factor receptor superfamily that inhibits osteoclastogenesis. We examined the effects of OPG administration on the distribution, ultrastructure and vacuolar-type H+-ATPase expression of osteoclasts and resulting trabecular bone loss in the femurs of ovariectomized (OVX) mice. Two-month-old female ddY mice were allocated to the following groups: (1) pretreatment base-line controls; (2) untreated sham-operated controls; (3) untreated OVX; and (4) OPG-administered OVX mice. Postoperatively, OPG (0.3 mg kg(-1) day(-1)) was intraperitoneally administered daily to OVX mice for 7 days. On postoperative day 7, all mice were sacrificed, and the dissected femurs were examined by means of light and immunoelectron microscopy and quantitative backscattered-electron image analysis. Backscattered-electron examination revealed that trabecular bone area/unit medullary area in untreated OVX mice was significantly lower than that of base-line control and sham-operated control mice. Compared with untreated OVX mice, OPG administration to OVX mice significantly increased trabecular bone area, which was similar to that of sham-operated control mice. Surprisingly, the number of TRAP-positive osteoclasts along the trabecular bone surfaces in OPG-administered OVX mice was not significantly decreased compared with that of sham-operated control and untreated OVX mice. Ultrastructurally, OPG administration caused disappearance of ruffled borders in most osteoclasts, but induced neither necrotic nor apoptotic changes. In addition, the expression of vacuolar-type H+-ATPase in osteoclasts was decreased by OPG administration. Our results suggest that low-dose OPG administration significantly reduces trabecular bone loss in OVX mice via impairment of the structure and bone resorbing activity of osteoclasts.
authors.affiliation: Department of Oral Histology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Shimizu-Ishiura
authors.forename: Fumi
authors.initials: F
authors.lastname: Kawana
authors.forename: Takahisa
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006023:Glycoproteins / Q000627:therapeutic use*; D051379:Mice / Q000601:surgery; D008854:Microscopy, Electron; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D010024:Osteoporosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D053244:Osteoprotegerin; D010052:Ovariectomy; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D011500:Protein Synthesis Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse; D025262:Vacuolar Proton-Translocating ATPases