title: Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption.
abstract: Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17beta-estradiol (E2) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats.
authors.affiliation: Laboratory of Mineralized Tissues, School of Medicine, University of Zagreb, Salata 11, 10 000 Zagreb.
authors.forename: Petra
authors.initials: P
authors.lastname: Simic
authors.forename: Jasminka Buljan
authors.initials: JB
authors.lastname: Culej
authors.forename: Iva
authors.initials: I
authors.lastname: Orlic
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
authors.forename: Natasa
authors.initials: N
authors.lastname: Draca
authors.forename: Radan
authors.initials: R
authors.lastname: Spaventi
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
mesh_terms: D000375:Aging; D000818:Animals; D015519:Bone Density; D001846:Bone Development; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage*; D001862:Bone Resorption; D004958:Estradiol / Q000378:metabolism; D005269:Femur / Q000473:pathology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014057:Tomography, X-Ray Computed
chemical_list: C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; C525818:Bmp6 protein, rat; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D004958:Estradiol