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
Jacobsen, Christina M; Barber, Lauren A; Ayturk, Ugur M et al. (2014) Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J Bone Miner Res 29:2297-306
Zhao, Liming; Shim, Joon W; Dodge, Todd R et al. (2013) Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading. Bone 54:35-43
Ayturk, Ugur M; Jacobsen, Christina M; Christodoulou, Danos C et al. (2013) An RNA-seq protocol to identify mRNA expression changes in mouse diaphyseal bone: applications in mice with bone property altering Lrp5 mutations. J Bone Miner Res 28:2081-93
Niziolek, Paul J; Farmer, Takeisha L; Cui, Yajun et al. (2011) High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. Bone 49:1010-9
Robling, Alexander G; Kedlaya, Rajendra; Ellis, Shana N et al. (2011) Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 152:2963-75
Cui, Yajun; Niziolek, Paul J; MacDonald, Bryan T et al. (2011) Lrp5 functions in bone to regulate bone mass. Nat Med 17:684-91
McAteer, Maureen E; Niziolek, Paul J; Ellis, Shana N et al. (2010) Mechanical stimulation and intermittent parathyroid hormone treatment induce disproportional osteogenic, geometric, and biomechanical effects in growing mouse bone. Calcif Tissue Int 86:389-96
Komatsu, David E; Mary, Michelle N; Schroeder, Robert Jason et al. (2010) Modulation of Wnt signaling influences fracture repair. J Orthop Res 28:928-36
Robling, Alexander G (2010) Muscle loss and bone loss: master and slave? Bone 46:272-3
Warden, Stuart J; Robling, Alexander G; Haney, Elizabeth M et al. (2010) The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Bone 46:4-12

Showing the most recent 10 out of 21 publications