Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people 50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment options for the disease require a greater understanding of the cellular events and signaling pathways that control bone metabolism. The proposed research capitalizes on a collection of missense mutations in 2-propeller 1 of the LDL-receptor-related protein 5 (LRP5), recently identified in several human families, that have a major impact on bone mass regulation. The long term goal of the proposed project is to identify new molecular targets, yielded from novel mouse models engineered with those mutations, for pharmacologic intervention aimed at improving bone mass and reducing fracture susceptibility. LRP5 has been postulated to participate in the canonical WNT signaling cascade (e.g., GSK32-mediated modulation of 2- catenin activity) in vitro, but our recent data indicates that alterations in canonical WNT signaling might not account for the anabolic effects of the HBM mutations. Discovery of the mechanism by which Lrp5 controls bone formation would lead to new approaches for improving bone mass. In this application, we propose to determine whether 2-catenin is required for the bone formation effects of Lrp5. We will use two novel knock-in mouse models of HBM disease. These mice, which are modeled after two of the LRP5 HBM human families, have either the G171V or the A214V amino acid substitutions knocked in to Lrp5. The mutations result in very high bone mass, driven completely by increased bone formation, with no change in bone resorption. We will test whether these two mutations are associated with increased bone formation when 2- catenin is deleted. Further, we will determine whether the bone formation phenotype of Lrp5 knockout mice can be rescued by constitutive activation of 2-catenin. Subsequently, we will determine the mechanism of action for the G171V and A214V mutations, which appear to have fundamentally different effects at the cellular and tissue levels. In this Merit application, we address these questions in order to identify new Lrp5-associated anabolic targets for improving bone health.

Public Health Relevance

Roughly 25% men over the age of 50 will suffer an osteoporotic fracture during their senior years, and the 1- year mortality rate following a hip fracture is nearly 2W as high for men as for women. One-fifth of those who were ambulatory before their hip fracture require long-term care afterward. Beyond their age, other lifestyle factors make veterans particularly susceptible to osteoporosis, including smoking, alcohol consumption, and an inactivity. Moreover, many Vietnam veterans were exposed to environmental factors during the war, such as the dioxin TCDD (found in Agent Orange), which put them at much greater risk for osteoporosis. Recently, the VA amended its adjudication regulation to establish a presumption of service connection for osteoporosis for former Prisoners of War (POWs) who were detained or interned for at least 30 days, and more recently, for those diagnosed with posttraumatic stress disorder (PTSD), and whose osteoporosis is at least 10% disabling. There is a clear need to identify new treatment options for veterans that suffer from low bone mass disease.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001478-04
Application #
8774177
Study Section
Endocrinology B (ENDB)
Project Start
2012-01-01
Project End
2015-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Rlr VA Medical Center
Department
Type
DUNS #
608434697
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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:
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
Kang, Kyung Shin; Hong, Jung Min; Robling, Alexander G (2016) Postnatal ?-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation. Bone 88:138-145
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

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