title: High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo.
abstract: Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). We previously reported the creation of two Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes ((8kb) Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes ((2.3kb) Col1a1-Dkk1). We observed that the (8kb) Dmp1-SOST transgene significantly lowered whole-body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone-formation rate (BFR) in wild-type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The (2.3kb) Col1a1-Dkk1 transgene significantly lowered whole-body BMD, BMC, and vertebral BV/TV in wild-type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM-causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1.
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
authors: Paul J
authors: PJ
authors: Niziolek
authors: The FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.|Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors: Bryan T
authors: BT
authors: MacDonald
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Rajendra
authors: R
authors: Kedlaya
authors: Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.|Departments of Orthopaedic Surgery and Genetics, Harvard Medical School, Boston, MA, USA.
authors: Minjie
authors: M
authors: Zhang
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Teresita
authors: T
authors: Bellido
authors: The FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.|Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors: Xi
authors: X
authors: He
authors: Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.|Departments of Orthopaedic Surgery and Genetics, Harvard Medical School, Boston, MA, USA.
authors: Matthew L
authors: ML
authors: Warman
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis (IUPUI), Indianapolis, IN, USA.|Richard L Roudebush VA Medical Center, Indianapolis, IN, USA.
authors: Alexander G
authors: AG
authors: Robling
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D055879:Gene Knock-In Techniques; D056426:Genetic Loci; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D009929:Organ Size / Q000235:genetics; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C486030:Sost protein, mouse
keywords: A214V; DKK1; G171V; HIGH BONE MASS (HBM); LRP5; OSTEOPOROSIS; SCLEROSTIN; SOST; WNT