Bone Marrow Fat Physiology in Relation to Skeletal Metabolism and Cardiometabolic Disease Risk in Children With Cerebral Palsy

Abstract Individuals with cerebral palsy exhibit neuromuscular complications and low physical activity levels. Adults with cerebral palsy exhibit a high prevalence of chronic diseases, which is associated with musculoskeletal deficits. Children with cerebral palsy have poor musculoskeletal accretion accompanied by excess bone marrow fat, which may lead to weaker bones. Mechanistic studies to determine the role of bone marrow fat on skeletal growth and maintenance and how it relates to systemic energy metabolism among individuals with cerebral palsy are lacking. In this review, we highlight the skeletal status in children with cerebral palsy and analyze the existing literature on the interactions among bone marrow fat, skeletal health, and cardiometabolic disease risk in the general population. Clinically vital questions are proposed, including the following: (1) Is the bone marrow fat in children with cerebral palsy metabolically distinct from typically developing children in terms of its lipid and inflammatory composition? (2) Does the bone marrow fat suppress skeletal acquisition? (3) Or, does it accelerate chronic disease development in children with cerebral palsy? (4) If so, what are the mechanisms? In conclusion, although inadequate mechanical loading may initiate poor skeletal development, subsequent expansion of bone marrow fat may further impede skeletal acquisition and increase cardiometabolic disease risk in those with cerebral palsy.

[1]  J. Pettitt,et al.  The skeletal cell‐derived molecule sclerostin drives bone marrow adipogenesis , 2018, Journal of cellular physiology.

[2]  Sung-Rae Cho,et al.  Patients with non-ambulatory cerebral palsy have higher sclerostin levels and lower bone mineral density than patients with ambulatory cerebral palsy. , 2017, Bone.

[3]  O. Naveiras,et al.  Bone marrow adipocytes promote the regeneration of stem cells and hematopoiesis by secreting SCF , 2017, Nature Cell Biology.

[4]  J. Heeren,et al.  Quantification of Bone Fatty Acid Metabolism and Its Regulation by Adipocyte Lipoprotein Lipase , 2017, International journal of molecular sciences.

[5]  M. Peterson,et al.  Multimorbidity in Middle-Aged Adults with Cerebral Palsy. , 2017, The American journal of medicine.

[6]  M. Kruger,et al.  Palmitoleic Acid Inhibits RANKL-Induced Osteoclastogenesis and Bone Resorption by Suppressing NF-κB and MAPK Signalling Pathways , 2017, Nutrients.

[7]  R. Shatla,et al.  Bone mineral density and insulin-like growth factor-1 in children with spastic cerebral palsy , 2017, Child's Nervous System.

[8]  J. Rodríguez,et al.  Characterization of Fatty Acid Composition in Bone Marrow Fluid From Postmenopausal Women: Modification After Hip Fracture , 2016, Journal of cellular biochemistry.

[9]  E. López-Huertas,et al.  Daily Intake of Milk Enriched with n-3 Fatty Acids, Oleic Acid, and Calcium Improves Metabolic and Bone Biomarkers in Postmenopausal Women , 2016, Journal of the American College of Nutrition.

[10]  O. MacDougald,et al.  Marrow Adipose Tissue: Trimming the Fat , 2016, Trends in Endocrinology & Metabolism.

[11]  O. MacDougald,et al.  Inside out: Bone marrow adipose tissue as a source of circulating adiponectin , 2016, Adipocyte.

[12]  M. Bozzali,et al.  Bone Marrow Lipid Profiles from Peripheral Skeleton as Potential Biomarkers for Osteoporosis: A 1H-MR Spectroscopy Study. , 2016, Academic radiology.

[13]  S. Cremers,et al.  Palmitic Acid Reduces Circulating Bone Formation Markers in Obese Animals and Impairs Osteoblast Activity via C16-Ceramide Accumulation , 2016, Calcified Tissue International.

[14]  M. Fahey,et al.  Musculoskeletal and Endocrine Health in Adults With Cerebral Palsy: New Opportunities for Intervention. , 2016, The Journal of clinical endocrinology and metabolism.

[15]  Ryan J Schulze,et al.  Hdac3 Deficiency Increases Marrow Adiposity and Induces Lipid Storage and Glucocorticoid Metabolism in Osteochondroprogenitor Cells , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  J. Ryan,et al.  Chronic Conditions in Adults With Cerebral Palsy. , 2015, JAMA.

[17]  M. Peterson,et al.  Greater Adipose Tissue Distribution and Diminished Spinal Musculoskeletal Density in Adults With Cerebral Palsy. , 2015, Archives of physical medicine and rehabilitation.

[18]  W. Malaisse,et al.  Oleate Abrogates Palmitate-Induced Lipotoxicity and Proinflammatory Response in Human Bone Marrow-Derived Mesenchymal Stem Cells and Osteoblastic Cells. , 2015, Endocrinology.

[19]  O. MacDougald,et al.  Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues , 2015, Nature Communications.

[20]  P. Hardouin,et al.  Understanding the local actions of lipids in bone physiology. , 2015, Progress in lipid research.

[21]  L. Goodyear,et al.  Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations , 2015, Diabetes.

[22]  P. Hardouin,et al.  Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles (EVs) , 2015, BMC Cell Biology.

[23]  C. Rosen,et al.  The bone-fat interface: basic and clinical implications of marrow adiposity. , 2015, The lancet. Diabetes & endocrinology.

[24]  R. Boyd,et al.  Differences in body composition according to functional ability in preschool-aged children with cerebral palsy. , 2015, Clinical nutrition.

[25]  C. Modlesky,et al.  Underdevelopment of trabecular bone microarchitecture in the distal femur of nonambulatory children with cerebral palsy becomes more pronounced with distance from the growth plate , 2015, Osteoporosis International.

[26]  B. Lecka-Czernik,et al.  Bone and fat: a relationship of different shades. , 2014, Archives of biochemistry and biophysics.

[27]  A. Caplan,et al.  Identification of a Subpopulation of Marrow MSC-Derived Medullary Adipocytes That Express Osteoclast-Regulating Molecules: Marrow Adipocytes Express Osteoclast Mediators , 2014, PloS one.

[28]  O. MacDougald,et al.  Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. , 2014, Cell metabolism.

[29]  H. Jick,et al.  Bone Fractures in Children with Autistic Spectrum Disorder , 2014, Journal of developmental and behavioral pediatrics : JDBP.

[30]  R. Parkkola,et al.  Vertebral bone marrow glucose uptake is inversely associated with bone marrow fat in diabetic and healthy pigs: [(18)F]FDG-PET and MRI study. , 2014, Bone.

[31]  D. Ornitz,et al.  Osx-Cre Targets Multiple Cell Types besides Osteoblast Lineage in Postnatal Mice , 2014, PloS one.

[32]  J. McGinley,et al.  Gait function and decline in adults with cerebral palsy: a systematic review , 2014, Disability and rehabilitation.

[33]  H. Düppe,et al.  Fractures in children with cerebral palsy: a total population study , 2013, Developmental medicine and child neurology.

[34]  Sara E Strecker,et al.  Osterix-Cre Labeled Progenitor Cells Contribute to the Formation and Maintenance of the Bone Marrow Stroma , 2013, PloS one.

[35]  Xiaojuan Li,et al.  Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  P. Scherer,et al.  Adiponectin, driver or passenger on the road to insulin sensitivity? , 2013, Molecular metabolism.

[37]  S. Cinti,et al.  Molecular and functional characterization of human bone marrow adipocytes. , 2013, Experimental hematology.

[38]  T. Rantalainen,et al.  Differential effects of exercise on tibial shaft marrow density in young female athletes. , 2013, The Journal of clinical endocrinology and metabolism.

[39]  Vilmundur Gudnason,et al.  Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults. , 2013, The Journal of clinical endocrinology and metabolism.

[40]  L. Jones,et al.  Dexamethasone-induced lipolysis increases the adverse effect of adipocytes on osteoblasts using cells derived from human mesenchymal stem cells. , 2013, Bone.

[41]  O. MacDougald,et al.  Marrow fat and bone--new perspectives. , 2013, The Journal of clinical endocrinology and metabolism.

[42]  T. Stijnen,et al.  Insulin Resistance and Risk of Incident Cardiovascular Events in Adults without Diabetes: Meta-Analysis , 2012, PloS one.

[43]  C. Burant,et al.  Secondary muscle pathology and metabolic dysregulation in adults with cerebral palsy. , 2012, American journal of physiology. Endocrinology and metabolism.

[44]  L. Joosten,et al.  Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. , 2012, Endocrinology.

[45]  H. Kronenberg,et al.  Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  L. Makowski,et al.  The inflammation highway: metabolism accelerates inflammatory traffic in obesity , 2012, Immunological reviews.

[47]  S. Heymsfield,et al.  Ethnic and sex differences in bone marrow adipose tissue and bone mineral density relationship , 2012, Osteoporosis International.

[48]  R. Müller,et al.  Increased marrow adiposity in premenopausal women with idiopathic osteoporosis. , 2012, The Journal of clinical endocrinology and metabolism.

[49]  P. Gressens,et al.  Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy? , 2012, The Lancet Neurology.

[50]  A. Zallone,et al.  Osteoblast and osteoclast crosstalks: from OAF to Ephrin. , 2012, Inflammation & allergy drug targets.

[51]  B. Lecka-Czernik Marrow fat metabolism is linked to the systemic energy metabolism. , 2012, Bone.

[52]  Y. Lu,et al.  Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. , 2012, Bone.

[53]  L. Joosten,et al.  The inflammasome puts obesity in the danger zone. , 2012, Cell metabolism.

[54]  Xiaojuan Li,et al.  Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus? , 2012, Journal of magnetic resonance imaging : JMRI.

[55]  Paul J. Williams,et al.  t10c12‐CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity , 2011, Journal of cellular physiology.

[56]  Jay J Cao Effects of obesity on bone metabolism , 2011, Journal of orthopaedic surgery and research.

[57]  T. Wren,et al.  Bone marrow fat is inversely related to cortical bone in young and old subjects. , 2011, The Journal of clinical endocrinology and metabolism.

[58]  M. Durkin,et al.  Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the Autism and Developmental Disabilities Monitoring Network. , 2011, Research in developmental disabilities.

[59]  M. Osaki,et al.  Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression. , 2011, Biomedical research.

[60]  W. Jee,et al.  Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. , 2011, Bone.

[61]  Ganesh V. Halade,et al.  Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice , 2011, Experimental Gerontology.

[62]  M. Bredella,et al.  Vertebral Bone Marrow Fat Is Positively Associated With Visceral Fat and Inversely Associated With IGF‐1 in Obese Women , 2011, Obesity.

[63]  Paul J. Williams,et al.  High fat diet-induced animal model of age-associated obesity and osteoporosis. , 2010, The Journal of nutritional biochemistry.

[64]  P. Davies,et al.  Energy expenditure and physical activity of ambulatory children with cerebral palsy and of typically developing children. , 2010, The American journal of clinical nutrition.

[65]  P. Hardouin,et al.  Human osteoblasts derived from mesenchymal stem cells express adipogenic markers upon coculture with bone marrow adipocytes. , 2010, Differentiation; research in biological diversity.

[66]  T. Wren,et al.  Bone acquisition in healthy young females is reciprocally related to marrow adiposity. , 2010, The Journal of clinical endocrinology and metabolism.

[67]  I. Morita,et al.  The effects of polyunsaturated fatty acids and their metabolites on osteoclastogenesis in vitro. , 2010, Prostaglandins & other lipid mediators.

[68]  J. Fonollá,et al.  Improvement of bone formation biomarkers after 1-year consumption with milk fortified with eicosapentaenoic acid, docosahexaenoic acid, oleic acid, and selected vitamins. , 2010, Nutrition research.

[69]  S. Enerbäck Human brown adipose tissue. , 2010, Cell metabolism.

[70]  B. Cannon,et al.  The changed metabolic world with human brown adipose tissue: therapeutic visions. , 2010, Cell metabolism.

[71]  J. Rodríguez,et al.  Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[72]  A. El-Sohemy,et al.  Regulation of osteoblast and adipocyte differentiation from human mesenchymal stem cells by conjugated linoleic acid. , 2009, The Journal of nutritional biochemistry.

[73]  Kevin J. Sheridan Osteoporosis in adults with cerebral palsy , 2009, Developmental medicine and child neurology.

[74]  Guoyin Feng,et al.  Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[75]  J. Kang,et al.  Endogenous n‐3 fatty acids protect ovariectomy induced bone loss by attenuating osteoclastogenesis , 2009, Journal of cellular and molecular medicine.

[76]  M. Bredella,et al.  Increased bone marrow fat in anorexia nervosa. , 2009, The Journal of clinical endocrinology and metabolism.

[77]  D. Yeung,et al.  A study of bone marrow and subcutaneous fatty acid composition in subjects of varying bone mineral density. , 2009, Bone.

[78]  M. Osaki,et al.  Bone marrow adipocytes support dexamethasone-induced osteoclast differentiation. , 2009, Biochemical and biophysical research communications.

[79]  C. Modlesky,et al.  Adipose tissue infiltration of skeletal muscle in children with cerebral palsy. , 2009, The Journal of pediatrics.

[80]  G. Daley,et al.  Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment , 2009, Nature.

[81]  C. Modlesky,et al.  Evaluation of the femoral midshaft in children with cerebral palsy using magnetic resonance imaging , 2009, Osteoporosis International.

[82]  J. Gimble,et al.  Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro , 2009, Journal of cellular and molecular medicine.

[83]  S. Watkins,et al.  Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism , 2008, Cell.

[84]  S. Mittelman,et al.  DIFFERENTIAL EFFECT OF MARROW ADIPOSITY AND VISCERAL AND SUBCUTANEOUS FAT ON CARDIOVASCULAR RISK IN YOUNG, HEALTHY ADULTS , 2008, International Journal of Obesity.

[85]  S. Mittelman,et al.  Reciprocal relation between marrow adiposity and the amount of bone in the axial and appendicular skeleton of young adults. , 2008, The Journal of clinical endocrinology and metabolism.

[86]  Russell S. Kirby,et al.  Prevalence of Cerebral Palsy in 8-Year-Old Children in Three Areas of the United States in 2002: A Multisite Collaboration , 2008, Pediatrics.

[87]  B. Riggs,et al.  Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women , 2008, Osteoporosis International.

[88]  C. Modlesky,et al.  Underdeveloped trabecular bone microarchitecture is detected in children with cerebral palsy using high-resolution magnetic resonance imaging , 2008, Osteoporosis International.

[89]  Giselle Chamberlain,et al.  Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing , 2007, Stem cells.

[90]  J. Volpe,et al.  Pathogenesis of cerebral white matter injury of prematurity , 2007, Archives of Disease in Childhood Fetal and Neonatal Edition.

[91]  Dongxu Sun,et al.  Effect of fish oil on bone mineral density in aging C57BL/6 female mice. , 2007, The Journal of nutritional biochemistry.

[92]  Laurence Vico,et al.  Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis. , 2007, Endocrinology.

[93]  S. B. Heymsfield,et al.  MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in Caucasian women , 2007, Osteoporosis International.

[94]  Ting Hong,et al.  The descriptive epidemiology of cerebral palsy. , 2006, Clinics in perinatology.

[95]  J. Woo,et al.  Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: A proton MR spectroscopy study , 2005, Journal of magnetic resonance imaging : JMRI.

[96]  Y. Wang,et al.  UCP1 deficiency increases susceptibility to diet‐induced obesity with age , 2005, Aging cell.

[97]  Kevin C McGill,et al.  Neuromuscular activation and motor-unit firing characteristics in cerebral palsy. , 2005, Developmental medicine and child neurology.

[98]  Stuart A Binder-Macleod,et al.  Voluntary muscle activation, contractile properties, and fatigability in children with and without cerebral palsy , 2005, Muscle & nerve.

[99]  Philip A Kern,et al.  Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. , 2003, Diabetes.

[100]  F. Miller,et al.  Fractures in Patients With Cerebral Palsy , 2003, Journal of pediatric orthopedics.

[101]  C. Modlesky,et al.  Does Exercise During Growth Have a Long-Term Effect on Bone Health? , 2002, Exercise and sport sciences reviews.

[102]  P. Rezaie,et al.  Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system , 2002, Neuropathology : official journal of the Japanese Society of Neuropathology.

[103]  M. Conaway,et al.  Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy. , 2002, Pediatrics.

[104]  S. Khosla,et al.  Minireview: the OPG/RANKL/RANK system. , 2001, Endocrinology.

[105]  Flemming Melsen,et al.  Cancellous Bone Remodeling Occurs in Specialized Compartments Lined by Cells Expressing Osteoblastic Markers , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[106]  E. Yalçin,et al.  Changes in Skeletal Maturation and Mineralization in Children With Cerebral Palsy and Evaluation of Related Factors , 2001, Journal of child neurology.

[107]  H. Song,et al.  Cross-sectional study of osteopenia with quantitative MR imaging and bone densitometry. , 2000, Radiology.

[108]  R. Shavelle,et al.  Causes of excess mortality in cerebral palsy , 1999, Developmental medicine and child neurology.

[109]  D. Strauss,et al.  Causes of excess mortality in cerebral palsy. , 1999 .

[110]  D. Damiano,et al.  Lower‐Extremity strength profiles in spastic cerebral palsy , 1998, Developmental medicine and child neurology.

[111]  B. Zemel,et al.  Energy expenditure of children and adolescents with severe disabilities: a cerebral palsy model. , 1996, The American journal of clinical nutrition.

[112]  A. Parfitt,et al.  Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. , 1996, The Journal of clinical investigation.

[113]  W. Greene,et al.  Bone-mineral density in children and adolescents who have spastic cerebral palsy. , 1995, The Journal of bone and joint surgery. American volume.

[114]  Ari Heinonen,et al.  Effect of Starting Age of Physical Activity on Bone Mass in the Dominant Arm of Tennis and Squash Players , 1995, Annals of Internal Medicine.

[115]  C. Devlin,et al.  Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. , 1992, Journal of cell science.

[116]  S. Moore,et al.  Red and yellow marrow in the femur: age-related changes in appearance at MR imaging. , 1990, Radiology.

[117]  J. Gimble The function of adipocytes in the bone marrow stroma. , 1990, The New biologist.

[118]  P. Meunier,et al.  Marrow changes in paraplegic patients , 1984, Calcified Tissue International.

[119]  R. Prout,et al.  Lipid analysis of rat enamel and dentine. , 1973, Archives of oral biology.

[120]  P Meunier,et al.  Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. , 1971, Clinical orthopaedics and related research.

[121]  G. Hudson Bone‐Marrow Volume in the Human Foetus and Newborn , 1965, British journal of haematology.

[122]  J. Emery,et al.  Regression of Bone‐Marrow Haemopoiesis from the Terminal Digits in the Foetus and Infant , 1964, British journal of haematology.

[123]  M. Nogueira-Barbosa,et al.  Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus. , 2017, European journal of endocrinology.

[124]  C. Modlesky,et al.  Cortical bone deficit and fat infiltration of bone marrow and skeletal muscle in ambulatory children with mild spastic cerebral palsy. , 2017, Bone.

[125]  S. Heymsfield,et al.  Comparison of the relationship between bone marrow adipose tissue and volumetric bone mineral density in children and adults. , 2014, Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry.

[126]  J. Gimble,et al.  Mechanisms of palmitate-induced lipotoxicity in human osteoblasts. , 2014, Endocrinology.

[127]  André Tchernof,et al.  Pathophysiology of human visceral obesity: an update. , 2013, Physiological reviews.

[128]  Matthew R Allen,et al.  Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. , 2012, Bone.

[129]  L. McCabe,et al.  Human bone marrow adiposity is linked with serum lipid levels not T1-diabetes. , 2012, Journal of diabetes and its complications.

[130]  Kim Van Naarden Braun,et al.  Prevalence of cerebral palsy: Autism and Developmental Disabilities Monitoring Network, three sites, United States, 2004. , 2009, Disability and health journal.

[131]  A. Rogol,et al.  Puberty, statural growth, and growth hormone release in children with cerebral palsy. , 2009, Journal of pediatric rehabilitation medicine.

[132]  T. Plesner,et al.  A physical mechanism for coupling bone resorption and formation in adult human bone. , 2008, The American journal of pathology.

[133]  Mary L Bouxsein,et al.  Mechanisms of Disease: is osteoporosis the obesity of bone? , 2006, Nature Clinical Practice Rheumatology.

[134]  L. Mosekilde,et al.  Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis , 2004, Biogerontology.

[135]  J. Marques Lower-extremity strength profiles in spastic cerebral palsy. , 2002, Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association.

[136]  R. Martin,et al.  Relationships between marrow fat and bone turnover in ovariectomized and intact rats. , 1991, Bone.