title: A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength.
abstract: Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A-mFc) in vivo. mBMPR1A-mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A-mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A-mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.
authors: Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.
authors: Marc
authors: M
authors: Baud'huin
authors: Nicolas
authors: N
authors: Solban
authors: Milton
authors: M
authors: Cornwall-Brady
authors: Dianne
authors: D
authors: Sako
authors: Yoshimi
authors: Y
authors: Kawamoto
authors: Katia
authors: K
authors: Liharska
authors: Darren
authors: D
authors: Lath
authors: Mary L
authors: ML
authors: Bouxsein
authors: Kathryn W
authors: KW
authors: Underwood
authors: Jeffrey
authors: J
authors: Ucran
authors: Ravindra
authors: R
authors: Kumar
authors: Eileen
authors: E
authors: Pobre
authors: Asya
authors: A
authors: Grinberg
authors: Jasbir
authors: J
authors: Seehra
authors: Ernesto
authors: E
authors: Canalis
authors: R Scott
authors: RS
authors: Pearsall
authors: Peter I
authors: PI
authors: Croucher
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000517:prevention & control*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053245:RANK Ligand / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; D008156:Luciferases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I