Nutritional-Induced Longitudinal Catch-Up Growth: A Focus on the Growth Plate, Growth-Related Genes, Autophagy, mTOR, and microRNAs



The association between nutrition and linear growth in children is well accepted: the growth of the human skeleton requires an adequate supply of many different nutritional factors and a close relationship exists between mechanisms regulating weight and those regulating linear growth. Children with malnutrition have significantly lower body weight and height than healthy subjects, as well as reduced levels of serum leptin, insulin, and insulin-like growth factor-I. Catch-up (CU) growth is a phase of accelerated growth following correction of a temporary growth-retarding endocrinological, nutritional, medical, or emotional disorder, which allowed children to resume their pre-illness growth curve. However, the mechanism that underlies the body’s “sensing” and “correction” of the growth delay as well as the exact mechanism whereby nutrition modulates cellular activity during bone elongation are still unclear. Several hormones, especially GH/IGF-I, leptin, and insulin, together with other as yet unidentified factors, affect local pathways that coordinate and couple chondrocyte proliferation and differentiation at the epiphyseal growth plate (EGP). Here we describe the effects of nutritional restriction and refeeding on the EGP, with a focus on growth-related genes. We also suggest the involvement of novel regulatory mechanisms in growth regulation including autophagy, mTOR, and microRNAs. A normal child is challenged with numerous episodes of growth-retarding causes (teeth eruption, minor infections, etc.), which are corrected without any long-standing effect. However, small alterations in the efficiency of the mechanism of the CU growth may lead eventually to significant differences in height. By understanding the mechanism of CU growth we may be able to design a better therapeutic regimen for children with growth disorders.


Food Restriction Hypertrophic Chondrocytes Protein Energy Malnutrition Protein Energy Malnutrition Epiphyseal Growth Plate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Catch up


Epiphyseal growth plate


Intrauterine growth retardation


Growth hormone


Growth hormone receptor


Growth hormone-releasing hormone


Hypoxia-inducible factor


HIF-responsive element


Insulin-like growth factor


Insulin-like growth factor receptor


Indian hedgehog


Idiopathic short stature




Protein energy malnutrition


Parathyroid hormone-related peptide





The authors wish to thank Gloria Ginzach for English editing.


  1. Accorsi PA, Munno A, et al. Role of leptin on growth hormone and prolactin secretion by bovine pituitary explants. J Dairy Sci. 2007;90:1683–91.PubMedCrossRefGoogle Scholar
  2. Alvarez-Garcia O, Carbajo-Perez E, Garcia E, Gil H, Molinos I, Rodriguez J, Ordonez FA, Santos F. Rapamycin retards growth and causes marked alterations in the growth plate of young rats. Pediatr Nephrol. 2007;22:954–61.PubMedCrossRefGoogle Scholar
  3. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.PubMedGoogle Scholar
  4. Baltimore D, Boldin MP, et al. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9:839–45.PubMedCrossRefGoogle Scholar
  5. Baumeister FA, Engelsberger I, Schulze A. Pancreatic agenesis as cause for neonatal diabetes mellitus. Klin Padiatr. 2005;217:76–81.PubMedCrossRefGoogle Scholar
  6. Ben-Eliezer M, Phillip M, Gat-Yablonski G. Leptin regulates chondrogenic differentiation in ATDC5 cell-line through JAK/STAT and MAPK pathways. Endocrine. 2007;32:235–44.PubMedCrossRefGoogle Scholar
  7. Bernstein E, Kim SY, et al. Dicer is essential for mouse development. Nat Genet. 2003;35:215–7.PubMedCrossRefGoogle Scholar
  8. Boersma B, Wit JM. Catch-up growth. Endocr Rev. 1997;18:646–61.PubMedCrossRefGoogle Scholar
  9. Buyukgebiz B, Ozturk Y, Yilmaz S, Arslan N. Serum leptin concentrations in children with mild protein-energy malnutrition and catch-up growth. Pediatr Int. 2004;46:534–8.PubMedCrossRefGoogle Scholar
  10. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.PubMedCrossRefGoogle Scholar
  11. Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet. 2007;8:93–103.PubMedCrossRefGoogle Scholar
  12. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401.PubMedCrossRefGoogle Scholar
  13. Cohen MM, Jr. Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling. Am J Med Genet. 2006;A 140:515–24.CrossRefGoogle Scholar
  14. Coupé B, Grit I, Darmaun D, Parnet P. The timing of “catch-up growth” affects metabolism and appetite regulation in male rats born with intra-uterine growth restriction. Am J Physiol Regul Integr Comp Physiol. 2009;297:R813–24.PubMedCrossRefGoogle Scholar
  15. Cruickshank J, Grossman DI, Peng RK, Famula TR, Oberbauer AM. Spatial distribution of growth hormone receptor, insulin-like growth factor-I receptor and apoptotic chondrocytes during growth plate development. J Endocrinol. 2005;184:543–53.PubMedCrossRefGoogle Scholar
  16. Cuellar TL, McManus MT. MicroRNAs and endocrine biology. J Endocrinol. 2005;187:327–32.PubMedCrossRefGoogle Scholar
  17. Esau C, Kang X, et al. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem. 2004;279:52361–5.PubMedCrossRefGoogle Scholar
  18. Even-Zohar N, Jacob J, Amariglio N, Rechavi G, Potievsky O, Phillip M, Gat-Yablonski G. Nutrition-induced catch-up growth increases hypoxia inducible factor 1alpha RNA levels in the growth plate. Bone. 2008;42:505–15.PubMedCrossRefGoogle Scholar
  19. Farnum CE, Lee AO, O’Hara K, Wilsman NJ. Effect of short-term fasting on bone elongation rates: an analysis of catch-up growth in young male rats. Pediatr Res. 2003;53:33–41.PubMedGoogle Scholar
  20. Fliesen T, Maiter D, Gerard G, Underwood LE, Maes M, Ketelslegers JM. Reduction of serum insulin-like growth factor-I by dietary protein restriction is age dependent. Pediatr Res. 1989;26:415–9.PubMedCrossRefGoogle Scholar
  21. Frederich RC, Lollmann B, et al. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest. 1995;96:1658–63.Google Scholar
  22. Gafni RI, Weise M, Robrecht DT, Meyers JL, Barnes KM, De-Levi S, Baron J. Catch-up growth is associated with delayed senescence of the growth plate in rabbits. Pediatr Res. 2001;50:618–23.PubMedCrossRefGoogle Scholar
  23. Gat-Yablonski G, Phillip M. Leptin and regulation of linear growth. Curr Opin Clin Nutr Metab Care. 2008;11:303–8.PubMedCrossRefGoogle Scholar
  24. Gat-Yablonski G, Ben-Ari T, Shtaif B, Potievsky O, Moran O, Eshet R, Maor G, Segev Y, Phillip M. Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth. Endocrinology. 2004;145:343–50.PubMedCrossRefGoogle Scholar
  25. Gat-Yablonski G, Shtaif B, Phillip M. Leptin stimulates parathyroid hormone related peptide expression in the endochondral growth plate. J Pediatr Endocrinol Metab. 2007;20:1215–22.PubMedCrossRefGoogle Scholar
  26. Gat-Yablonski G, Shtaif B, Abraham E, Phillip M. Nutrition-induced catch-up growth at the growth plate. J Pediatr Endocrinol Metab. 2008;21:879–93.PubMedCrossRefGoogle Scholar
  27. Gat-Yablonski G, Gavan-Yackobovitz M, Phillip M. Nutrition and Bone Growth in Pediatrics. Endocrinol Metab Clin North Am. 2009;38:565–86.PubMedCrossRefGoogle Scholar
  28. Grisaru-Granovsky S, Samueloff A, Elstein D. The role of leptin in fetal growth: a short review from conception to delivery. Eur J Obstet Gynecol Reprod Biol. 2008;136:146–50.PubMedCrossRefGoogle Scholar
  29. Han ES, Hickey M. Microarray evaluation of dietary restriction. J Nutr. 2005;135:1343–6.PubMedGoogle Scholar
  30. Harfe BD, McManus MT, Mansfield JH, Hornstein E, Tabin CJ. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci USA. 2005;102:10898–903.PubMedCrossRefGoogle Scholar
  31. He Z, Sontheimer EJ. “siRNAs and miRNAs”: a meeting report on RNA silencing. RNA. 2004;10:1165–73.PubMedCrossRefGoogle Scholar
  32. Heinrichs C, Colli M, Yanovski JA, Laue L, Gerstl NA, Kramer AD, Uyeda JA, Baron J. Effects of fasting on the growth plate: systemic and local mechanisms. Endocrinology. 1997;138:5359–65.PubMedCrossRefGoogle Scholar
  33. Hermanussen M, Rol de Lama MA, Romero AP, Ruiz CA, Burmeister J, Tresguerres JA. Differential catch-up in body weight and bone growth after short-term starvation in rats. Growth Regul. 1996;6:230–7.PubMedGoogle Scholar
  34. Hoggard N, Mercer JG, et al. Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization. Biochem Biophys Res Commun. 1997;232:383–7.Google Scholar
  35. Hunziker EB, Wagner J, et al. Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J Clin Invest. 1994;93:1078–86.Google Scholar
  36. Iwaniec UT, Boghossian S, et al. Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice. Peptides. 2007;28:1012–9.Google Scholar
  37. Jin L, Burguera BG, et al. Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab. 1999;84:2903–11.Google Scholar
  38. Kappeler L, De Magalhaes Filho C, Leneuve P, Xu J, Brunel N, Chatziantoniou C, Le Bouc Y, Holzenberger M. Early postnatal nutrition determines somatotropic function in mice. Endocrinology. 2009;150:314–23.PubMedCrossRefGoogle Scholar
  39. Kay’s SK, Hindmarsh PC. Catch-up growth: an overview. Pediatr Endocrinol Rev. 2006;3:365–78.PubMedGoogle Scholar
  40. Kim J, Inoue K, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007;317:1220–24.PubMedCrossRefGoogle Scholar
  41. Kobayashi T, Lu J, et al. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci USA. 2008;105:1949–54.PubMedCrossRefGoogle Scholar
  42. Kume K, Satomura K, Nishisho S, Kitaoka E, Yamanouchi K, Tobiume S, Nagayama M. Potential role of leptin in endochondral ossification. J Histochem Cytochem. 2002;50:159–69.PubMedCrossRefGoogle Scholar
  43. LaPaglia N, Steiner J, Kirsteins L, Emanuele M, Emanuele N. Leptin alters the response of the growth hormone releasing factor- growth hormone – insulin-like growth factor-I axis to fasting. J Endocrinol. 1998;159:79–83.PubMedCrossRefGoogle Scholar
  44. Lowe WL Jr, Adamo M, Werner H, Roberts CT Jr, LeRoith D. Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and binding. J Clin Invest. 1989;84:619–26.PubMedCrossRefGoogle Scholar
  45. Luque RM, Huang ZH, Shah B, Mazzone T, Kineman RD. Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. Am J Physiol Endocrinol Metab. 2007;292:E891–9.PubMedCrossRefGoogle Scholar
  46. Maor G, Rochwerger M, Segev Y, Phillip M. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Miner Res. 2002;17:1034–43.PubMedCrossRefGoogle Scholar
  47. Maqsood AR, Trueman JA, Whatmore AJ, Westwood M, Price DA, Hall CM, Clayton PE. The relationship between nocturnal urinary leptin and gonadotrophins as children progress towards puberty. Horm Res. 2007;68:225–30.PubMedCrossRefGoogle Scholar
  48. Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway. Endocrinology. 2007;148:3419–25.PubMedCrossRefGoogle Scholar
  49. Miller RA, Chang Y, Galecki AT, Al-Regaiey K, Kopchick JJ, Bartke A. Gene expression patterns in calorically restricted mice: partial overlap with long-lived mutant mice. Mol Endocrinol. 2002;16:2657–66.PubMedCrossRefGoogle Scholar
  50. Mosier HD, Jr, Jansons RA. Growth hormone during catch-up growth and failure of catch-up growth in rats. Endocrinology. 1976;98:214–9.PubMedCrossRefGoogle Scholar
  51. Nakajima R, Inada H, Koike T, Yamano T. Effects of leptin to cultured growth plate chondrocytes. Horm Res. 2003;60:91–8.PubMedCrossRefGoogle Scholar
  52. Ong K, Kratzsch J, Kiess W, Dunger D. Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate. J Clin Endocrinol Metab. 2002;87:1041–4.PubMedCrossRefGoogle Scholar
  53. Papagiannakopoulos T, Kosik KS. MicroRNAs: regulators of oncogenesis and stemness. BMC Med. 2008;6:15.PubMedCrossRefGoogle Scholar
  54. Pauley KM, Cha S, et al. MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun. 2009;32:189–94.Google Scholar
  55. Phillip M, Moran O, et al. Growth without growth hormone. J Pediatr Endocrinol Metab. 2002;15(Suppl 5):1267–72.Google Scholar
  56. Poy MN, Eliasson L, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–30.Google Scholar
  57. Prader A, Tanner JM, von HG. Catch-up growth following illness or starvation. An example of developmental canalization in man. J Pediatr. 1963;62:646–59.PubMedCrossRefGoogle Scholar
  58. Robson H, Siebler T, Shalet SM, Williams GR. Interactions between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth. Pediatr Res. 2002;52:137–47.PubMedGoogle Scholar
  59. Sanchez CP, He YZ. Bone growth during rapamycin therapy in young rats. BMC Pediatr. 2009;9:3.PubMedCrossRefGoogle Scholar
  60. Schickel R, Boyerinas B, et al. MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008;27:5959–74.PubMedCrossRefGoogle Scholar
  61. Schipani E. Hypoxia and HIF-1 alpha in chondrogenesis. Semin Cell Dev Biol. 2005;16:539–46.PubMedCrossRefGoogle Scholar
  62. Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissues Organs. 2009;189:88–92.PubMedCrossRefGoogle Scholar
  63. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept. 2000;92:73–8.PubMedCrossRefGoogle Scholar
  64. Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun. 2004;313:443–6.PubMedCrossRefGoogle Scholar
  65. Tuddenham L, Wheeler G, Ntounia-Fousara S, Waters J, Hajihosseini MK, Clark I, Dalmay T. The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett. 2006;580:4214–7.PubMedCrossRefGoogle Scholar
  66. Underwood LE, Clemmons DR, Maes M, D'Ercole AJ, Ketelslegers JM. Regulation of somatomedin-C/insulin-like growth factor I by nutrients. Horm Res. 1986;24:166–76.PubMedCrossRefGoogle Scholar
  67. Vega RB, Matsuda K, et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell. 2004;119:555–6.PubMedCrossRefGoogle Scholar
  68. Walenkamp MJ, Wit JM. Single gene mutations causing SGA. Best Pract Res Clin Endocrinol Metab. 2008;22:433–46.PubMedCrossRefGoogle Scholar
  69. Wienholds E, Kloosterman WP, et al. MicroRNA expression in zebrafish embryonic development. Science. 2005;309:310–1.PubMedCrossRefGoogle Scholar
  70. Zhang J, Jima DD, et al. Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood. 2009;113:4586–94.PubMedCrossRefGoogle Scholar
  71. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.The Jesse Z and Sara Lea Shafer Institute for Endocrinology and DiabetesNational Center for Children’s Diabetes, Schneider Children’s Medical Center of IsraelPetah TikvaIsrael
  2. 2.Felsenstein Medical Research CenterPetah TikvaIsrael
  3. 3.Sackler School of Medicine, Tel Aviv UniversityTel AvivIsrael
  4. 4.The Jesse Z and Sara Lea Shafer Institute for Endocrinology and DiabetesNational Center for Childhood Diabetes, Schneider Children’s Medical Center of IsraelPetah TikvaIsrael
  5. 5.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations