Fragility fractures in the elderly represent a substantial source of morbidity and mortality to our aging population and are a great cost to society as a whole. The ability to heal fractures decreases with age where at one extreme, a skeletally immature child can heal a fracture in several weeks and at the other, an octogenarian may take several months or more to heal the same fracture. At the cellular and molecular level, there are several lines of evidence suggesting that Notch signaling is an important determinant in bone formation and fracture healing. Additionally, studies have shown that decreased Notch signaling with aging is responsible for reduced muscle regeneration with aging. We hypothesize that the decrease in fracture healing with aging is associated with alterations in Notch signaling. To test this hypothesis we propose two specific aims. For the first aim we will characterize and compare Notch expression and signaling in fracture healing using young and chronologically aged mice. For the second aim we will characterize and compare the histologic and biomechanical progression of fracture healing in aged mice with Notch signaling increased. We will increase Notch signaling in a mouse model that has the Notch intracellular domain (NICD - the active signaling component) driven by the activity of Cre-recombinase. This work will provide the foundation for further investigation of the Notch pathway as a modifiable event in the acceleration of fracture healing in the elderly.

Public Health Relevance

Fragility fractures represent a significant cause of morbidity in the elderly. These fractures take much longer to heal and with greater morbidity than fractures in the young. The work proposed in this study using a mouse model will investigate whether increasing Notch signaling can be used to promote healing of fractures in geriatric patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG040670-02
Application #
8313898
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
Program Officer
Williams, John
Project Start
2011-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$80,000
Indirect Cost
$30,000
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mutyaba, Patricia L; Belkin, Nicole S; Lopas, Luke et al. (2014) Notch signaling in mesenchymal stem cells harvested from geriatric mice. J Orthop Trauma 28 Suppl 1:S20-3