The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and strength. LRP5 loss-of-function mutations cause severely low bone mass, while specific missense mutations cause extremely high bone mass (HBM). Our research program has generated data indicating that LRP5 functions within bone as part of the mechanotransduction pathway. The research proposed in this application is intended to pinpoint precisely which cell type(s) in bone require LRP5 for mechanotransduction, to determine when and how much Lrp5 HBM alleles can improve mechanotransduction and other bone properties when the HBM alleles are activated after birth, to uncover which potential up-stream modulators of the LRP5 - SOST axis are required during mechanotransduction, and to learn how the cells that experience altered LRP5 activity in response to changes in mechanical load send signals to effector cells at bone surfaces to either produce new bone or resorb unneeded bone. We will use our recently developed mouse models (e.g., conditionally activated Lrp5 HBM alleles) and mouse models recently developed by other investigators, in order to answer the questions posed in our four Aims. Our goal is to understand the where's, when's, which's, and how's of LRP5 action in mechanotransduction, which can ultimately lead to the discovery of new therapies that improve human bone health.

Public Health Relevance

This research aims to understand the pathway in which the cell surface receptor LRP5 functions to regulate bone mass and bone strength in humans. Genetic absence of LRP5 causes very low bone mass, while other mutations in this protein can cause very high bone mass. We will study mice that express different forms of LRP5 to determine where, when, and how it participates in mechanotransduction, and consequently, affects bone mass and fracture susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053237-08
Application #
8513914
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2005-09-30
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$567,830
Indirect Cost
$150,234
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ross, Ryan D; Mashiatulla, Maleeha; Robling, Alexander G et al. (2016) Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status. Calcif Tissue Int 98:149-57
Kedlaya, Rajendra; Kang, Kyung Shin; Hong, Jung Min et al. (2016) Adult-Onset Deletion of β-Catenin in (10kb)Dmp1-Expressing Cells Prevents Intermittent PTH-Induced Bone Gain. Endocrinology 157:3047-57
Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J et al. (2016) Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta. Bone 90:127-32
Kang, Kyung Shin; Hong, Jung Min; Robling, Alexander G (2016) Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation. Bone 88:138-45
Alam, Imranul; Alkhouli, Mohammed; Gerard-O'Riley, Rita L et al. (2016) Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice. Endocrinology 157:722-36
Niziolek, Paul J; Bullock, Whitney; Warman, Matthew L et al. (2015) Missense Mutations in LRP5 Associated with High Bone Mass Protect the Mouse Skeleton from Disuse- and Ovariectomy-Induced Osteopenia. PLoS One 10:e0140775
Melville, Katherine M; Robling, Alexander G; van der Meulen, Marjolein C H (2015) In vivo axial loading of the mouse tibia. Methods Mol Biol 1226:99-115
Goodman, Craig A; Hornberger, Troy A; Robling, Alexander G (2015) Bone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms. Bone 80:24-36
Niziolek, Paul J; MacDonald, Bryan T; Kedlaya, Rajendra et al. (2015) High Bone Mass-Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo. J Bone Miner Res 30:1822-30
Cui, Yajun; Niziolek, Paul J; MacDonald, Bryan T et al. (2014) Reply to Lrp5 regulation of bone mass and gut serotonin synthesis. Nat Med 20:1229-30

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