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 #
2R01AR053237-06A1
Application #
8238922
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
2011-09-19
Budget End
2012-07-31
Support Year
6
Fiscal Year
2011
Total Cost
$611,214
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Organized Research Units
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bird, Ian M; Kim, Susie H; Schweppe, Devin K et al. (2018) The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects. Development 145:
Kang, Kyung Shin; Hong, Jung Min; Horan, Daniel J et al. (2018) Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism. Bone 120:166-175
Williams, Justin N; Kambrath, Anuradha Valiya; Patel, Roshni B et al. (2018) Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification. J Bone Miner Res 33:930-944
Caetano-Lopes, J; Lessard, S G; Hann, S et al. (2017) Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease. Bone 105:253-261
Shao, Yu; Hernandez-Buquer, Selene; Childress, Paul et al. (2017) Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology 158:2722-2740
Alam, Imranul; Reilly, Austin M; Alkhouli, Mohammed et al. (2017) Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes. Calcif Tissue Int 100:361-373
Piemontese, Marilina; Almeida, Maria; Robling, Alexander G et al. (2017) Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2:
Williams, Bart O; Warman, Matthew L (2017) CRISPR/CAS9 Technologies. J Bone Miner Res 32:883-888
Bullock, Whitney A; Robling, Alexander G (2017) WNT-mediated Modulation of Bone Metabolism: Implications for WNT Targeting to Treat Extraskeletal Disorders. Toxicol Pathol 45:864-868
Kedlaya, Rajendra; Kang, Kyung Shin; Hong, Jung Min et al. (2016) Adult-Onset Deletion of ?-Catenin in (10kb)Dmp1-Expressing Cells Prevents Intermittent PTH-Induced Bone Gain. Endocrinology 157:3047-57

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