The population with cerebral palsy (CP) is expected to expand in the coming decades. This is a major public issue because individuals with CP have an early and devastating onset of age-related chronic diseases, which is associated with osteoporosis and other musculoskeletal diseases. In childhood, individuals with CP have a weak and underdeveloped musculoskeletal system. The inadequate accretion of muscle and bone becomes progressively worse throughout growth and leads to a heightened susceptibility of low-energy fracture among this pediatric population. Therefore, it is imperative to identify mechanisms that suppress skeletal acquisition throughout growth in children with CP in order to develop target-specific interventions to promote musculoskeletal accretion and overall health. Recent and emerging evidence suggests that children with CP have an excess accumulation of bone marrow fat, which is characterized by elevated total bone marrow fat and/or higher bone marrow lipid saturated index- proportion of saturated fatty acids to total fatty acids. Both elevated bone marrow fat and altered bone marrow lipid composition are associated with irregular adipokine secretion, inflammation, poor skeletal metabolism, and increased fracture risk among non-CP populations. The role of altered bone marrow lipid, adipokine, and inflammation on skeletal acquisition is unknown for skeletally fragile pediatric populations, such as children with CP. The long-term goal of our research is to maximize musculoskeletal accretion throughout growth and development, and preserve musculoskeletal mass and function throughout the adult lifespan among individuals with CP. The specific goal of this project is to identify the bone-fat crosstalk among children with CP by determining the biological role that altered bone marrow lipid, adipokine, and inflammation has on skeletal acquisition.
The specific aims of this project will be accomplished by using bone marrow collected during routine posterior spinal fusion surgery from children with and without CP, and ST2 cells, which is a murine marrow derived mesenchymal stem cell line with osteogenic and adipogenic potential.
Specific Aim 1 will identify the bone marrow saturated index and bone marrow adipokine and inflammatory profiles in children with CP, as compared to age- and sex-matched children without CP.
For Specific Aim 2, we will continue to refine a new methodology that will allow us to test if alterations in bone marrow fat, adipokine, and inflammatory profiles specific to CP impair skeletal acquisition by culturing ST2 cells with bone marrow secretome from children with and without CP. The goal of the proposed study is aligned with multiple high-priority research areas from the Pediatric Growth and Nutrition Branch of NICHD: ?determinants of peak bone mass and peak bone strength? and ?hormonal regulation of bone, muscle, and adipose tissue?. Study findings will identify new insights of suppressed skeletal acquisition in children with CP, and provide empirical evidence for our team to develop a targeted intervention to bolster skeletal development.

Public Health Relevance

Cerebral palsy (CP) is the most common physical disability of childhood and is associated with low physical activity, excess body fat, poor musculoskeletal development, and a high prevalence of low-energy fracture. In their adult years, individuals with CP have a profound musculoskeletal disease profile, which is associated with an accelerated development of noncommunicable diseases. Information obtained from this study will identify key biological mechanisms contributing to suppressed musculoskeletal acquisition in children with CP, which will inform the development of target-specific interventions aimed at enhancing skeletal accretion in children with CP and other physical disabilities.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Winer, Karen
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University of Michigan Ann Arbor
Physical Medicine & Rehab
Schools of Medicine
Ann Arbor
United States
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