title: Missense Mutations in LRP5 Associated with High Bone Mass Protect the Mouse Skeleton from Disuse- and Ovariectomy-Induced Osteopenia.
abstract: The low density lipoprotein receptor-related protein-5 (LRP5), a co-receptor in the Wnt signaling pathway, modulates bone mass in humans and in mice. Lrp5 knock-out mice have severely impaired responsiveness to mechanical stimulation whereas Lrp5 gain-of-function knock-in and transgenic mice have enhanced responsiveness to mechanical stimulation. Those observations highlight the importance of Lrp5 protein in bone cell mechanotransduction. It is unclear if and how high bone mass-causing (HBM) point mutations in Lrp5 alter the bone-wasting effects of mechanical disuse. To address this issue we explored the skeletal effects of mechanical disuse using two models, tail suspension and Botulinum toxin-induced muscle paralysis, in two different Lrp5 HBM knock-in mouse models. A separate experiment employing estrogen withdrawal-induced bone loss by ovariectomy was also conducted as a control. Both disuse stimuli induced significant bone loss in WT mice, but Lrp5 A214V and G171V were partially or fully protected from the bone loss that normally results from disuse. Trabecular bone parameters among HBM mice were significantly affected by disuse in both models, but these data are consistent with DEXA data showing a failure to continue growing in HBM mice, rather than a loss of pre-existing bone. Ovariectomy in Lrp5 HBM mice resulted in similar protection from catabolism as was observed for the disuse experiments. In conclusion, the Lrp5 HBM alleles offer significant protection from the resorptive effects of disuse and from estrogen withdrawal, and consequently, present a potential mechanism to mimic with pharmaceutical intervention to protect against various bone-wasting stimuli.
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Niziolek
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Whitney
authors.initials: W
authors.lastname: Bullock
authors.affiliation: Department of Orthopaedic Surgery, Children's Hospital, Boston, Massachusetts, United States of America.|Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Massachusetts, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.affiliation: Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.|Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis (IUPUI), Indianapolis, Indiana, United States of America.|Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, United States of America.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics / Q000502:physiology*; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001905:Botulinum Toxins / Q000633:toxicity; D004195:Disease Models, Animal; D004967:Estrogens / Q000172:deficiency / Q000502:physiology; D005260:Female; D005269:Femur / Q000473:pathology; D055879:Gene Knock-In Techniques; D006801:Humans; D007103:Immobilization / Q000009:adverse effects; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology; D051379:Mice; D020125:Mutation, Missense; D015663:Osteoporosis, Postmenopausal / Q000473:pathology / Q000517:prevention & control; D010052:Ovariectomy / Q000009:adverse effects; D010243:Paralysis / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D017354:Point Mutation; D013314:Stress, Mechanical; D016474:Weight-Bearing
chemical_list: D004967:Estrogens; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D001905:Botulinum Toxins