Among the diseases and disorders associated with advancing age, one of the most debilitating is the loss of normal homeostatic function of the skeleton. This is particularly true with osteoporosis, wherein hip fractures are invariably associated with chronic pain, reduced mobility, disability, and an increased degree of dependence. In addition, up to 20% of patients die within the first year following hip fractures. Less than half of those who survive the hip fracture regain their previous level of function. As th world's population is continuing to age at a rapid rate, the incidence of skeletal disease is expected to rise substantially. Current medical and surgical therapies for age-related bone disease are suboptimal, the majority relying on the implantation of foreign materials that are subject to a host of complications including infection and further fractures. For this reason, we are focusing on the stem cell population within bone as a potential target to understand and harness the body's intrinsic potential to heal disorders of the skeleton. Stem cells are the cells that are responsible for maintaining normal homeostasis in an organ, and for regeneration following injury. We have identified a skeletal stem cell population which is capable of forming all of the components of the skeleton - bone, cartilage and the marrow stroma. It is proposed that the reduced regenerative capacity that occurs with aging is a multifaceted problem, perhaps due to intrinsic changes in the stem cells themselves or changes in the environment in which the cells reside - the stem cell niche, or perhaps a combination of these.
Our first aim i s to characterize the effects of aging on normal bone homeostasis in young and old mice, exploring parameters such as bone turnover and bone mineral density. We have devised a novel injury model to identify age-related differences in response to injury. With this data we will then look a the role of the systemic environment on the skeletal system, specifically exploring the role of the niche in maintaining an efficient pool of skeletal stem cells using a heterochronic parabiosis model where a young and an old mouse will be surgically paired. This study will allow for identification of novel mechanisms responsible for skeletal aging and will allow for identification of clinically-translatable ways of harnessing the intrinsic regenerative potential of stem cells in the skeleton system to reduce the biomedical burden currently associated with age-related skeletal disease.

Public Health Relevance

The world's population is aging at an alarming rate, and the frequency of osteoporosis, fractures, cartilage defects, myelodysplasia- all disease linked to defects in skeletal-lineage cells is skyrocketing. We have recently identified and prospectively isolated a stem cell population from mouse limbs that is capable of the clonal generation of all of the components of the skeleton that we term the mouse skeletal stem cell (mSSC). We also isolated the mSSC- derived progenitors for bone, cartilage and stromal stem cell. We believe a study of skeletal aging and its relation to mSSC and its downstream lineages as described in this proposal will provide a unique perspective on understanding the biology of aging that could play an instrumental role in our collective efforts to meet this emerging medical challenge.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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National Institute on Aging Initial Review Group (NIA)
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Williams, John
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Gulati, Gunsagar S; Murphy, Matthew P; Marecic, Owen et al. (2018) Isolation and functional assessment of mouse skeletal stem cell lineage. Nat Protoc 13:1294-1309
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