Osteogenesis imperfecta (OI) is a genetic disease of type I collagen or collagen-related proteins leading to severe bone fragility. While much is known regarding the genetic mutations leading to OI, treatment strategies have been limited primarily to anti-resorptive interventions originally developed for osteoporosis. There is currentl no effective anabolic treatment option for OI patients. The recent discovery of the protein sclerostin as a negative regulator of osteoblast activity has led to the development of anabolic sclerostin antibodies. For sclerostin antibody (SclAb) therapy to be effective in treating OI, it must activate osteoblasts harboring a collagen defect, increase bone mass, and reduce bone fragility characteristic of the disease. The objectives of this proposal are to understand the differential effects of SclAb therapy on bone cell activity, mass, and material quality when compared to bisphosphonate (BP) treatment in a mouse model of OI. The Brtl/+ mouse reproduces the cellular, biomechanical, and aging phenotype of the OI patient, and has been effectively used to evaluate BP therapies for OI. In this proposal, the role of BP and SclAb antibody in governing tissue mass and material properties will be evaluated. Pre-clinical treatment and combination therapies will be evaluated. The central hypothesis of this proposal is that SclAb therapy will decreases bone brittleness, and thus bone fragility, will require protective BP therapy to prevent transitory gains in bone mass from diminishing over time, but will not be blunted by prior or co-therapy with BP. However, pre- or co-therapy with BP may induce changes that persist with SclAb therapy, potentially placing the skeleton at risk for complications observed when treating with BP alone. Using fluorescence-guided biomechanical models designed to test bone brittleness at multiple hierarchical levels, the impact of these treatment options will be quantified based on drug timing and tissue age. Results from this study will directly impact future clinical treatment strategies for OI patients. Furthermore, these studis will yield critical data identifying how regulatory factors that govern osteoblast and osteoclast activity can influence tissue quality parameters at multiple size scales in the OI skeleton and wil be important for other diseases such as osteoporosis, for which BP use is commonplace, and SclAb therapy is proposed.

Public Health Relevance

This proposal will pursue an anabolic treatment strategy for the pediatric bone disease osteogenesis imperfecta through use of sclerostin antibody therapy. Functional implications of this therapy such as changes in bone mass, brittleness, and cell activity will be determined and compared to therapies currently in use, and combination therapy will be pursued to optimize therapeutic outcome. It is expected that the results from this proposal will define important treatment strategies for the osteogenesis imperfecta population, as well as answer critical basic science questions regarding how bone brittleness is regulated over multiple hierarchical size scales.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR062522-01A1
Application #
8395429
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2012-09-24
Project End
2017-06-30
Budget Start
2012-09-24
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$339,563
Indirect Cost
$114,563
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Olvera, Diana; Stolzenfeld, Rachel; Marini, Joan C et al. (2018) Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model. J Bone Miner Res 33:1272-1282
Mertz, E L; Makareeva, E; Mirigian, L S et al. (2016) Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model. Matrix Biol 52-54:29-42
Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D et al. (2016) Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age. Bone 84:222-229
Perosky, Joseph E; Khoury, Basma M; Jenks, Terese N et al. (2016) Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model. Bone 93:79-85
Sinder, Benjamin P; Salemi, Joseph D; Ominsky, Michael S et al. (2015) Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment. Bone 71:115-23
Jepsen, Karl J; Schlecht, Stephen H; Kozloff, Kenneth M (2014) Are we taking full advantage of the growing number of pharmacological treatment options for osteoporosis? Curr Opin Pharmacol 16:64-71
Sinder, B P; White, L E; Salemi, J D et al. (2014) Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength. Osteoporos Int 25:2097-107
Cabral, Wayne A; Perdivara, Irina; Weis, MaryAnn et al. (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465
Sinder, Benjamin P; Eddy, Mary M; Ominsky, Michael S et al. (2013) Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J Bone Miner Res 28:73-80