title: Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta.
abstract: The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA; Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA; Division of Genetics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Jacobsen
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Barber
authors.forename: Ugur M
authors.initials: UM
authors.lastname: Ayturk
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Roberts
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Deal
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weis
authors.forename: David
authors.initials: D
authors.lastname: Eyre
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010012:Osteogenesis; D010013:Osteogenesis Imperfecta / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C486030:Sost protein, mouse; D003094:Collagen
keywords: ANABOLICS; CELL/TISSUE SIGNALING; DISEASES AND DISORDERS OF BONE; GENETIC ANIMAL MODELS; OSTEOGENESIS IMPERFECTA; PARACRINE PATHWAYS; WNT/BETA-CATENIN/LRPS