Nutrition and Catch-up Growth

Rakefet Pando, Galia Gat-Yablonski, and Moshe Phillip

ongitudinal growth of the long bones in the postnatal period

occurs in the epiphyseal growth plates (EGP), located in the
proximal and distal parts of the long bones. Among the numerous
growth factors, local and systemic, that regulate EGP growth are
growth hormone (GH) and insulin-like growth factor 1, insulin,
thyroid hormones, sex steroids, and others. However, additional, as
yet uncharacterized growth factors may also exist because changes
in the above-mentioned growth factors do not explain all of the
growth abnormalities. Indeed, growth without GH has also been
described and the compensating factor not identified, thus
suggesting alternative regulatory systems that control linear growth
(1).
The effect of nutrition on linear growth is well established.
Growth stunting constitutes the most common effect of malnutrition, and numerous reports describe considerable height gain with
food supplementation. However, because most studies were performed in severely malnourished children, it was impossible to
dissect the effect of protein deficiency from deficiency of the other
nutrients required in childrens diet, namely phosphorus, calcium,
zinc, potassium, and other micronutrients (2).
To this day an average of 33% of all children younger than
5 years of age in the developing countries have linear growth
retardation or stunting due to chronic malnutrition, which is caused
by food shortage as well as by infectious diseases. Malnutrition is
also associated with developmental delay, including cognitive
deficits, poorer school achievement, and lower IQ. In younger
children it is associated with conduct, poorer attention, and poorer
social skills at school (3). Most studies were performed on malnourished children in developing countries and only a few were
performed in developed countries; however, no significant breakthrough was made in the last decades to understand the precise
association between nutrition and growth.
Deciphering the mechanisms that translate the signals of
energetic resources to a signal that allows growth may allow the
development of novel therapeutic regimen for children with idiopathic growth abnormalities.

CATCH-UP GROWTH
Catch-up (CU) growth is defined as height velocity above
the normal statistical limits for age and/or maturity during a defined
period of time, following a transient period of growth inhibition.
Resolution of growth-inhibiting condition is followed by a period of
spontaneous CU growth and, depending on the age of the child, may
From the Tel-Aviv University Research Center for Nutrition, Growth and
Development, Israel.
Address correspondence and reprint requests to Prof Moshe Phillip, The
Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes,
National Center for Childhood Diabetes, Schneider Childrens Medical
Center of Israel, 14 Kaplan St, Petah Tikva 49202, Israel (e-mail:
mosheph@post.tau.ac.il).
The authors report no conflicts of interest.
Copyright # 2010 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3181f7bfe1

JPGN

Volume 51, Supplement 3, December 2010

lead to correct growth. One excellent example for nutrition-induced

CU growth is in childhood celiac disease. In these children, there is
remarkable CU growth shortly after the onset of a gluten-free diet.
Although several hormones have been shown to be affected
by nutritional manipulations, CU growth is probably an intrinsic
capability of the EGP (4). In our attempts to study the mechanisms
governing nutritional-induced CU growth in the EGP, we subjected
prepubertal rodents (rats and mice) to 10 days of 40% food
restriction, followed by a renewal of the regular food supply for
up to 7 days. We found a dramatic difference in weight between the
control and the restricted groups, as well as a significant difference
in the length of the tibias. The EGP height was significantly lower in
the restricted group, and a height change was observed in all cellular
zones. Under these conditions, the changes were partially reversible
because refeeding led to an instantaneous increase in body weight,
which was accompanied by an increase in tibial and EGP length
(5,6).
Among the hormones known to be affected by nutritional
manipulation, we decided to focus on leptin, a hormone secreted
from the adipocytes. It was found to be involved in the regulation of
food intake and body weight as well as of bone density. Leptin leads
to reduced food consumption and reduced weight gain in rodents.
We have shown that under leptin treatment, leptin increased the
length of the tibia, the overall size of the EGP, and stimulated
proliferation activity in the chondrocytes of the EGP compared with
pair-fed animals. The length of the tibia increased significantly in
the leptin-treated animals compared with the untreated controls.
Although it was previously described that leptin affects growth
centrally by stimulating GH secretion through its effect on GHreleasing hormone, we have shown that the effect of leptin was
independent of insulin-like growth factor 1 and that leptin has a
local, direct, GH-independent stimulatory effect on the EGP
through its receptor (7). We have shown that leptins effect on
the growth-plate chondrocytes is specifically mediated through
ERK1/2 and STAT3 (8).
Leptin appears to be an important mediator between nutrition
and growth and may play an important role in CU growth. However,
further studies suggested that leptin alone is not enough to explain
the major changes during nutrition-induced CU growth, and we are
still searching for other possible mediators.

NUTRITION AND THE EPIPHYSEAL GROWTH

PLATE
Examining the processes occurring in the EGP during CU
growth would enable us to characterize the most important pathways for growth acceleration occurring during CU.
Using an Affymetrix expression microarray, we analyzed
changes in gene expression during food restriction and CU growth
(5). The results showed changes in expression in hundreds of genes,
from which we focused only on those showing a decrease in
expression in the food-restricted group and a concomitant increase
in expression in the CU group, compared with the control group. We
identified among these genes the transcription factor hypoxiainducible factor 1a and several of its downstream targets,
suggesting that hypoxia-inducible factor 1a is a possible mediator

S129

Copyright 2010 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

Pando et al

JPGN

between nutrition and growth and may play an important role in

CU growth.
Further studies suggested the involvement of additional
regulatory mechanisms, such as microRNAs (miRNAs) and epigenetic regulation. The first are small nonprotein-coding RNAs,
measuring approximately 21 to 23 nucleotides in length, that
negatively regulate the expression of a large portion of proteinencoding and nonprotein-encoding genes at the posttranscriptional
level. Each miRNA can regulate 1 to several mRNA transcripts, and
conversely, a single mRNA may be regulated by 1 to several
miRNA sequences. The central role of miRNAs in skeletal development was demonstrated in mice devoid of the cytoplasmic
RNAse III Dicer enzyme, an essential enzyme in the metabolism
of miRNAs, in their cartilage. These animals showed that Dicer is
required for the formation of normal mouse limbs (9). In addition,
several miRNAs were shown to be involved in metabolism; thus, it
is reasonable to suggest a regulatory role for miRNAs in nutritionalinduced growth regulation of the EGP.
Epigenetic mechanism, defined as DNA methylation patterns
and associated posttranscriptional modifications of histones, is
thought to influence the programming of gene expression profiles.
In the growth plate, histone deacetylase (HDAC) 4 was recently
shown to be essential for the hypertrophy process. Furthermore, it
was shown that the cartilage-specific miR-140 regulates HDAC4 in
growth plate, thus suggesting a complex mode of epigenetic
regulation. Another class of HDACs, the sirtuins, are highly conserved enzymes that use nicotinamide adenine dinucleotide
(NAD) to deacetylate a number of histone and nonhistone substrates. Recently, it was shown that both SIRT1 and SIRT6 are
increased in response to long-term energy restriction in several
organs, suggesting that similar effect can occur in the EGP (10).

SUMMARY
Longitudinal bone growth at the growth plate is governed by
a complex network of signals; however, to this day, the exact
mechanism by which nutrition affects growth has not been eluci-

S130

Volume 51, Supplement 3, December 2010

dated. CU growth is a fascinating capability of the growth plate that

is associated with systemic as well as local growth factors, microRNAs, and epigenetic mechanisms. By using innovative experimental approaches we aim to decipher the regulatory signals that
mediate the effect of nutrition on CU growth. Understanding these
processes may lead to the development of novel therapeutic regimines and diagnostic approaches to treat children with idiopathic
growth abnormalities, especially when the response to GH treatment is not satisfactory.

REFERENCES
1. Phillip M, Moran O, Lazar L. Growth without growth hormone.
J Pediatr Endocrinol Metab 2002;15(Suppl 5):126772.
2. Rosado JL. Separate and joint effects of micronutrient deficiencies on
linear growth. J Nutr 1999;129(2S Suppl):531S3S.
3. Walker SP, Wachs TD, Gardner JM, et al. Child development: risk
factors for adverse outcomes in developing countries. Lancet
2007;369:14557.
4. Gafni RI, Weise M, Robrecht DT, et al. Catch-up growth is associated
with delayed senescence of the growth plate in rabbits. Pediatr Res
2001;50:61823.
5. Even-Zohar N, Jacob J, Amariglio N, et al. Nutrition-induced catch-up
growth increases hypoxia inducible factor 1 alpha RNA levels in the
growth plate. Bone 2008;42:50515.
6. Gat-Yablonski G, Shtaif B, Abraham E, et al. Nutrition-induced catchup growth at the growth plate. J Pediatr Endocrinol Metab 2008;
21:87993.
7. Gat-Yablonski G, Ben-Ari T, Shtaif B, et al. Leptin reverses the
inhibitory effect of caloric restriction on longitudinal growth. Endocrinology 2004;145:34350.
8. Ben-Eliezer M, Phillip M, Gat-Yablonski G. Leptin regulates chondrogenic differentiation in ATDC5 cell-line through JAK/STAT and MAPK
pathways. Endocrine 2007;32:23544.
9. Harfe BD, McManus MT, Mansfield JH, et al. The RNaseIII enzyme
Dicer is required for morphogenesis but not patterning of the vertebrate
limb. Proc Natl Acad Sci U S A 2005;102:108981103.
10. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes
mammalian cell survival by inducing the SIRT1 deacetylase. Science
2004;305:3902.

www.jpgn.org

Copyright 2010 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.