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Nutrition and Catch-up Growth

Rakefet Pando, Galia Gat-Yablonski, and Moshe Phillip

L ongitudinal growth of the long bones in the postnatal periodoccurs in the epiphyseal growth plates (EGP), located in theproximal and distal parts of the long bones. Among the numerousgrowth factors, local and systemic, that regulate EGP growth aregrowth hormone (GH) and insulin-like growth factor 1, insulin,thyroid hormones, sex steroids, and others. However, additional, asyet uncharacterized growth factors may also exist because changesin the above-mentioned growth factors do not explain all of thegrowth abnormalities. Indeed, growth without GH has also beendescribed and the compensating factor not identified, thussuggesting 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 malnu-trition, and numerous reports describe considerable height gain withfood supplementation. However, because most studies were per-formed in severely malnourished children, it was impossible todissect the effect of protein deficiency from deficiency of the othernutrients required in childrens diet, namely phosphorus, calcium,zinc, potassium, and other micronutrients (2).

To this day an average of 33% of all children younger than5 years of age in the developing countries have linear growthretardation or stunting due to chronic malnutrition, which is caused

by food shortage as well as by infectious diseases. Malnutrition isalso associated with developmental delay, including cognitivedeficits, poorer school achievement, and lower IQ. In younger

children it is associated with conduct, poorer attention, and poorersocial skills at school (3). Most studies were performed on mal-nourished children in developing countries and only a few were

performed in developed countries; however, no significant break-through was made in the last decades to understand the preciseassociation between nutrition and growth.

Deciphering the mechanisms that translate the signals ofenergetic resources to a signal that allows growth may allow thedevelopment of novel therapeutic regimen for children with idio-

pathic growth abnormalities.

CATCH-UP GROWTH

Catch-up (CU) growth is defined as height velocity abovethe 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 ofspontaneous CU growth and, depending on the age of the child, may

lead to correct growth. One excellent example for nutrition-inducedCU growth is in childhood celiac disease. In these children, there isremarkable CU growth shortly after the onset of a gluten-free diet.

Although several hormones have been shown to be affectedby nutritional manipulations, CU growth is probably an intrinsiccapability of the EGP(4). In our attempts to study the mechanismsgoverning nutritional-induced CU growth in the EGP, we subjected

prepubertal rodents (rats and mice) to 10 days of 40% foodrestriction, followed by a renewal of the regular food supply forup to 7 days. We found a dramatic difference in weight between thecontrol and the restricted groups, as well as a significant differencein the length of the tibias. The EGP height was significantlylower inthe restricted group, and a height change was observed in all cellularzones. 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 nutritionalmanipulation, we decided to focus on leptin, a hormone secretedfrom the adipocytes. It was found to be involved in the regulation offood intake and body weight as well as of bone density. Leptin leadsto reduced food consumption and reduced weight gain in rodents.We have shown that under leptin treatment, leptin increased thelength of the tibia, the overall size of the EGP, and stimulated

proliferation activity in the chondrocytes of the EGP compared withpair-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 growthcentrally by stimulating GH secretion through its effect on GH-releasing hormone, we have shown that the effect of leptin wasindependent of insulin-like growth factor 1 and that leptin has alocal, direct, GH-independent stimulatory effect on the EGPthrough its receptor (7). We have shown that leptins effect onthe growth-plate chondrocytes is specifically mediated throughERK1/2 and STAT3(8).

Leptin appears to be an important mediator between nutritionand growth and may play an important role in CU growth. However,further studies suggested that leptin alone is not enough to explainthe major changes during nutrition-induced CU growth, and we arestill searching for other possible mediators.

NUTRITION AND THE EPIPHYSEAL GROWTH

PLATE

Examining the processes occurring in the EGP during CUgrowth would enable us to characterize the most important path-ways for growth acceleration occurring during CU.

Using an Affymetrix expression microarray, we analyzedchanges 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 inexpression in the food-restricted group and a concomitant increasein expression in the CU group, compared with the control group. Weidentified among these genes the transcription factor hypoxia-inducible factor 1a and several of its downstream targets,

suggesting that hypoxia-inducible factor 1ais a possible mediator

From the Tel-Aviv University Research Center for Nutrition, Growth andDevelopment, Israel.

Address correspondence and reprint requests to Prof Moshe Phillip, TheJesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes,National Center for Childhood Diabetes, Schneider Childrens MedicalCenter 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 PediatricGastroenterology, Hepatology, and Nutrition

DOI:10.1097/MPG.0b013e3181f7bfe1

JPGN Volume 51, Supplement 3, December 2010 S129

mailto:mosheph@post.tau.ac.ilhttp://dx.doi.org/10.1097/MPG.0b013e3181f7bfe1http://dx.doi.org/10.1097/MPG.0b013e3181f7bfe1mailto:mosheph@post.tau.ac.il

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between nutrition and growth and may play an important role inCU growth.

Further studies suggested the involvement of additionalregulatory mechanisms, such as microRNAs (miRNAs) and epi-genetic 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 protein-encoding and nonprotein-encoding genes at the posttranscriptionallevel. Each miRNA can regulate 1 to several mRNA transcripts, andconversely, a single mRNA may be regulated by 1 to severalmiRNA sequences. The central role of miRNAs in skeletal devel-opment was demonstrated in mice devoid of the cytoplasmicRNAse III Dicer enzyme, an essential enzyme in the metabolismof miRNAs, in their cartilage. These animals showed that Dicer isrequired for the formation of normal mouse limbs(9). In addition,several miRNAs were shown to be involved in metabolism; thus, itis reasonable to suggest a regulatory role for miRNAs in nutritional-induced growth regulation of the EGP.

Epigenetic mechanism, defined as DNA methylation patternsand associated posttranscriptional modifications of histones, isthought to influence the programming of gene expression profiles.

In the growth plate, histone deacetylase (HDAC) 4 was recentlyshown to be essential for the hypertrophy process. Furthermore, itwas shown that the cartilage-specific miR-140 regulates HDAC4 ingrowth plate, thus suggesting a complex mode of epigeneticregulation. Another class of HDACs, the sirtuins, are highly con-served enzymes that use nicotinamide adenine dinucleotide(NAD) to deacetylate a number of histone and nonhistone sub-strates. Recently, it was shown that both SIRT1 and SIRT6 areincreased in response to long-term energy restriction in severalorgans, suggesting that similar effect can occur in the EGP(10).

SUMMARY

Longitudinal bone growth at the growth plate is governed bya complex network of signals; however, to this day, the exact

mechanism by which nutrition affects growth has not been eluci-

dated. CU growth is a fascinating capability of the growth plate thatis associated with systemic as well as local growth factors, micro-RNAs, and epigenetic mechanisms. By using innovative exper-imental approaches we aim to decipher the regulatory signals thatmediate the effect of nutrition on CU growth. Understanding these

processes may lead to the development of novel therapeutic regi-

mines and diagnostic approaches to treat children with idiopathicgrowth abnormalities, especially when the response to GH treat-ment is not satisfactory.

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