There is an urgent need to develop novel approaches to accelerate osteogenesis for the treatment of skeletal injury and disease. Combat troops and aging Veterans alike suffer from devastating orthopaedic injuries. While the young soldier suffering from a blast injury requires difficult limb reconstruction due to massive bone and soft tissue loss, the senior Veteran suffering from age-related bone loss is incapacitated by osteoporotic fractures, which are often associated with diminished osteogenic capacity, delayed healing, and non-union. Challenges in both acute trauma- and age-related fracture repairs converge on one critical deficiency: diminished ability to make bone due to a depleted stem cell pool. Autologous bone grafting, the gold standard for replenishing the stem cell pool in young healthy patients, can be unpredictable in cases of extreme tissue loss and in older patients. This is where our motivation lies: to mobilize and recruit a patient's own stem cells to the site of injury, and then activate these cells to produce bone in a timely manner. Our studies focus on a soluble stem cell recruitment factor, SDF-1, and its role as a paracrine signal regulating bone homeostasis and regeneration in response to mechanical loading and injury. The overall objective of this work is to determine the role of SDF-1 signaling during osteogenesis and regeneration using both loss-of-function models and exogenous SDF-1 treatment. Our central hypothesis is that SDF-1 acts as a paracrine mediator of progenitor recruitment and osteogenic differentiation in load- and injury-induced osteogenesis. We further hypothesize that SDF-1 treatment can accelerate bone repair in aged mice, a model of diminished regenerative capacity, possibly by enhancing cellular recruitment. To our hypotheses, we propose the following Specific Aims: (1) Determine the influence of osteoblast- and osteocyte-expressed SDF-1 on skeletal homeostasis and load-induced osteogenesis; (2) Determine the influence of osteoblast- and osteocyte-expressed SDF-1 on bone regeneration; and (3) Demonstrate that locally delivered SDF-1 can augment bone regeneration in aged mice, a model of suboptimal healing. If our hypotheses are correct, our studies will provide convincing evidence that SDF-1 works in a paracrine fashion in bone, a finding that would significantly advance our understanding of skeletal homeostasis and serve as a basis for developing therapeutic protocols to treat devastating orthopaedic injuries and disease in our Veterans.

Public Health Relevance

Combat troops and aging Veterans alike suffer from devastating orthopaedic injuries. While the young soldier suffering from a blast injury requires difficult limb reconstruction due to massive bone and soft tissue loss, the senior Veteran suffering from age-related bone loss is incapacitated by osteoporotic fractures, which are often associated with diminished osteogenic capacity, delayed healing, and non-union. Challenges in both acute trauma- and age-related fracture repairs converge on one critical deficiency: an inadequate number of osteopotent stem cells at the site of injury. The proposed studies represent translational work focused on utilizing a stem cell recruitment factor to regulate and enhance skeletal homeostasis and regeneration through cell recruitment and osteogenic differentiation.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX001500-04
Application #
9555823
Study Section
Translational Rehab (Basic) (RRD0)
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
VA Medical Center
Department
Type
DUNS #
070501002
City
New York
State
NY
Country
United States
Zip Code
10010
Liu, Chao; Cui, Xin; Ackermann, Thomas M et al. (2016) Osteoblast-derived paracrine factors regulate angiogenesis in response to mechanical stimulation. Integr Biol (Camb) 8:785-94