Fragility fractures continue to cause significant morbidity and mortality in our aging population particularly because delayed healing and non-union during fracture healing is more common in the elderly. The ability to heal fractures decreases with age and effective therapies to enhance fracture healing are still needed. Aging also leads to significant changes in the immune system and the role of aging immune cells in the impairment of bone regeneration has not been examined. Our proposal will examine the hypothesis that age-related changes in myeloid cells promote dysfunctional bone regeneration during fracture repair in the elderly. We propose that while macrophages are beneficial to bone repair in young mice, in aged mice, the changes in macrophage phenotype and function lead to a detrimental effect of macrophages on bone regeneration. Our proposal focuses on determining how changes in macrophages with aging affect their functional interactions with osteoblasts and mesenchymal stem cells in bone regeneration. A long-term goal is the development of therapeutics directed at macrophages that will enhance fracture repair in geriatric patients.
Our specific aims are: 1) Determine the effect of aging on osteal macrophages in the promotion of osteoblast differentiation and function. 2) Demonstrate the cell type(s) responsible for the "rescue" of fracture healing in older animals by bone marrow transplant from young animals. 3) Determine the effect of aging on macrophage and mesenchymal stem cell (MSC) interactions and determine the requirement for the myeloid cell receptor TREM2 in macrophage: MSC interactions

Public Health Relevance

Fractures in the elderly are a significant cause of morbidity with a greater incidence of delayed and non-union healing compared with younger individuals. Insufficient bone formation that occurs with age remains incompletely understood. Aging also leads to significant changes in immune cells and the effects of immune cell aging on bone regeneration have not been directly explored. Our proposal focuses on determining how changes in macrophages with aging affect functional interactions with osteoblasts and mesenchymal stem cells in bone regeneration with the long-term goal of developing therapeutics directed at macrophages to enhance fracture repair in geriatric patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG046282-01
Application #
8616534
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (A1))
Program Officer
Williams, John
Project Start
2013-09-30
Project End
2017-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$196,250
Indirect Cost
$71,250
Name
University of California San Francisco
Department
Orthopedics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hankenson, K D; Zimmerman, G; Marcucio, R (2014) Biological perspectives of delayed fracture healing. Injury 45 Suppl 2:S8-S15
Charles, Julia F; Nakamura, Mary C (2014) Bone and the innate immune system. Curr Osteoporos Rep 12:1-8
Nakamura, Mary C (2014) CIITA: a master regulator of adaptive immunity shows its innate side in the bone. J Bone Miner Res 29:287-9