The genetic disorder Osteogenesis Imperfecta (OI) is characterized by low bone mass that predisposes children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that encode type 1 collagen. Current medical therapies for patients with OI are mostly anti-catabolic, acting by preventing bone turnover to increase bone mass. Unfortunately, these therapies are limited and inadequate. In proof of principle experiments, I have found that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway leads to significant increases in bone mass and bone strength in two mouse models of OI. In the present application, I intend 1) to precisely define the mechanism(s) by which enhanced LRP5 signaling improves bone properties in these mouse models of OI, 2) to determine whether enhanced LRP5 signaling can improve bone properties in other mouse models of OI that are due to different type 1 collagen mutational mechanisms, and 3) to test whether prenatal administration of a neutralizing monoclonal antibody against sclerostin, an endogenous inhibitor of LRP5, is able to effect further improvements in bone properties and provide protection against immunogenicity-induced treatment resistance in comparison to postnatal anti-sclerostin antibody therapy. By addressing these aims, I will determine whether enhancing LRP5 signaling improves bone strength by increasing bone formation or by altering the repertoire of matrix proteins that are secreted by OI osteoblasts. I will also identify whether the type of mutation that causes OI determines whether enhancing LRP5 signaling will be beneficial or detrimental to human patients. Finally, using a mouse OI model, I will identify therapeutic strategies that best improve bone properties while minimizing the side effects of therapy.

Public Health Relevance

Osteogenesis Imperfecta (OI) is a disorder of low bone mass and frequent fractures for which current medical therapies are limited. Increasing low density lipoprotein receptor related-protein 5 (LRP5) signaling improves bone density and strength in two mouse models of OI by increasing bone formation. This proposal aims to define how LRP5 signaling improves bone strength in mouse models of OI, to define which types of mutations are most likely to benefit from therapies targeting the LRP5 pathway, and to identify therapeutic strategies using mouse models of OI that will provide the most benefit to human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AR063813-01
Application #
8425622
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Sharrock, William J
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$129,330
Indirect Cost
$9,580
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Kedlaya, Rajendra; Veera, Shreya; Horan, Daniel J et al. (2013) Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome. Sci Transl Med 5:211ra158