Chronic skeletal pain is a frequent companion of aging. In large part this is because the mass, quality, and strength of human bone peaks at 25-30 years of age and declines thereafter. Thus, by the time most humans are 60, normally non-traumatic, low impact falls can result in fracture of the hip, wrist, or vertebrae. Fractures in oler individuals are frequently painful and heal at significantly slower rates than in the young. For example, in older individuals with hip fractures the fractured bone usually never fully heals, is frequently accompanied by chronic skeletal pain, and most individuals never fully recover their pre-fracture functional status and quality of life. Currently, disorders and aging of the bone are one of the most common causes of chronic pain and long-term physical disabilities in the United States and the world. In large part this is because we know very little about the mechanisms that drive age-related bone pain and bone healing. As a result, we have remarkably few mechanism-based analgesics to control the pain or anabolic therapies to accelerate healing following an age- related bone fracture. In the present proposal, our goal is to begin to develop a mechanism-based understanding of what drives age-related fracture pain and bone healing. To accomplish these goals we will use a model of bone fracture pain and bone healing in the young vs. old male and female mice. This model will allow us to simultaneously explore bone fracture healing, skeletal pain behaviors, changes in sensory and sympathetic nerve fiber expression and sprouting, and the bone microenvironment in the normal and fractured bone. Importantly, the mouse model closely mirrors the pain and bone healing that occurs in humans. A key aspect of the application is that we will be focusing on old mice, as with age there is a marked increase in bone fractures, skeletal pain, and bone fracture associated morbidity / mortality.
Our specific aims are: 1) begin to elucidate the specific cells and factors that drive age-related fracture pain and bone healing; 2) determine the role that stromal cell factors, including nerve growth factor (NGF) and sclerostin, play in driving fracture pain and reducing fracture healing in the young vs. old bone. Our experience in working at the nerve / bone interface, the robust nature of the mouse bone fracture model, and the comparison of young vs. old offers a unique opportunity to increase our understanding of the mechanisms that drive age-related fracture pain / bone healing. If successful, these studies may help in the development of novel therapies that can more effectively treat age-related bone fractures.

Public Health Relevance

Skeletal pain is a frequent companion of aging. This project will focus on exploring the mechanisms that drive bone fracture pain / bone healing. If successful, this proposal has the potential to fundamentally transform our understanding of skeletal pain and how we treat and prevent age-related pain and bone fractures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023970-30
Application #
9649256
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Mohapatra, Durga Prasanna
Project Start
1987-04-01
Project End
2020-08-31
Budget Start
2019-03-01
Budget End
2020-08-31
Support Year
30
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Chartier, Stephane R; Mitchell, Stefanie A T; Majuta, Lisa A et al. (2018) The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur. Neuroscience 387:178-190
Majuta, Lisa A; Mitchell, Stefanie A T; Kuskowski, Michael A et al. (2018) Anti-nerve growth factor does not change physical activity in normal young or aging mice but does increase activity in mice with skeletal pain. Pain 159:2285-2295
Chartier, Stephane R; Mitchell, Stefanie At; Majuta, Lisa A et al. (2017) Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain 13:1744806917745465
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain 158:605-617
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Mice with cancer-induced bone pain show a marked decline in day/night activity. Pain Rep 2:e614
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2016) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery induced pain. Pain :
Thompson, Michelle L; Chartier, Stephane R; Mitchell, Stefanie A et al. (2016) Preventing painful age-related bone fractures: Anti-sclerostin therapy builds cortical bone and increases the proliferation of osteogenic cells in the periosteum of the geriatric mouse femur. Mol Pain 12:
Guedon, Jean-Marc G; Longo, Geraldine; Majuta, Lisa A et al. (2016) Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain 157:1239-47
Thompson, Michelle L; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W (2016) Sclerostin Immunoreactivity Increases in Cortical Bone Osteocytes and Decreases in Articular Cartilage Chondrocytes in Aging Mice. J Histochem Cytochem 64:179-89
Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane et al. (2015) Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. Pain 156:1692-702

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