Skip to Main Content
Skip Nav Destination
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

In mammals, after a period of growth inhibition, body growth often does not just return to a normal rate but actually exceeds the normal rate, resulting in catch-up growth. Recent evidence suggests that catch-up growth occurs because growth-inhibiting conditions delay progression of the physiological mechanisms that normally cause body growth to slow and cease with age. As a result, following the period of growth inhibition, tissues retain a greater proliferative capacity than normal, and therefore grow more rapidly than normal for age. There is evidence that this mechanism contributes both to catch-up growth in terms of body length, which involves proliferation in the growth plate, and to catch-up growth in terms of organ mass, which involves proliferation in multiple nonskeletal tissues.

Growth impairment can result from many systemic disorders, including endocrine, nutritional, gastrointestinal, cardiac, pulmonary, and renal disease. If these conditions resolve, growth velocity often does not just return to normal but actually exceeds the normal rate for age, causing the child's body size to re-approach the pre-illness growth trajectory [1]. This tendency to rapid linear growth that occurs after a period of growth inhibition is termed catch-up growth. Clinically, this phenomenon has been observed in a variety of circumstances including hypothyroidism, malnutrition (celiac disease, anorexia nervosa) and glucocorticoid excess [2]. It occurs both in terms of height, implying rapid growth at the growth plates, and in terms of organ size, implying rapid growth in multiple other tissues.

Bone elongation is the result of chondrocyte proliferation and further differentiation in the growth plates. Growth plates are found in tubular bones and vertebrae but not in the intramembranous bones of the face and skull. The growth plate is composed of three principal layers, the resting zone, the proliferative zone, and the hypertrophic zone [3]. Resting zone chondrocytes act as progenitor cells capable of producing clones of proliferative chondrocytes [4]. These proliferative cells, which are aligned in columns parallel to the long axis of the bone, replicate repeatedly but then undergo terminal differentiation and enlarge to form the hypertrophic zone. This hyperplasia and hypertrophy of chondrocytes, combined with cartilage matrix synthesis contributes to generation of new cartilage. The newly formed cartilage is then invaded by blood vessels and bone cells and thus remodeled into bone tissue. The net effect is bone elongation. The regulation of skeletal growth at the growth plate is complex and involves systemic and local mechanisms, including hormones, genetic and growth factors, environment and nutrition [5].

Catch-up growth occurs at the growth plate. Transient impairment of longitudinal bone growth is followed by accelerated bone elongation. Because bone length determines overall body length, this accelerated growth at the growth plate is responsible for catch-up growth in terms of body stature. Catch-up growth in children's height following illness or malnutrition was described more than 50 years ago [1, 6].

Tanner [7], one of the pioneers in the field of childhood growth, hypothesized that catch-up growth involves a central nervous system mechanism that compares actual body size to an age-appropriate set point. According to this ‘sizostat’ hypothesis, a circulating factor is produced by growing tissues in a concentration that reflects the size of the child. A central nervous system ‘sizostat’ compares this concentration to an age-appropriate set point and then modulates the growth rate to bring the actual body size closer to its set point. Thus, if a child is too small for age, the mechanism senses this abnormality and initiates catch-up growth.

However, subsequent data suggest that catch-up growth at the growth plate is due to a local, rather than a systemic mechanism. In rabbits, growth inhibition in a single growth plate, induced by local dexamethasone infusion, is followed by local catch-up growth in the affected growth plate [8]. This local catch-up growth is not readily explained by a systemic mechanism involving the central nervous system and circulating factors but instead suggests a mechanism intrinsic to the growth plate itself.

Recent work suggests that catch-up growth in the growth plate is related to the developmental process of growth plate senescence [9, 10]. This term refers to the physiologic loss of function combined with structural involution that the growth plate undergoes during juvenile life. With increasing age, there is a progressive decline in both chondrocyte proliferation and in the overall height of the growth plate, associated with a decreased number of proliferative and hypertrophic chondrocytes per column. As the proliferative rate declines, the rate of longitudinal bone growth decreases [11, 12].

The developmental program of growth plate senescence appears to be driven, not by time per se, but rather by growth. Growth-inhibiting conditions, such as glucocorticoid excess in rabbits [13] or hypothyroidism in rats [9], or tryptophan deficiency in rats [10], slow the process of growth plate senescence. This slowing involves structural changes in the growth plate, such as the decline in the number of chondrocytes in each zone, functional changes, such as the decline in proliferation rate, and molecular changes, such as the decline in Igf2 mRNA expression [9]. These findings imply that, when growth-inhibiting conditions resolve, the growth plates are less senescent than normal and therefore proliferate at a rate that is greater than normal for age, resulting in catch-up growth.

Indirect evidence suggests that linear catch-up growth in humans, as well as laboratory animals, is related to delayed growth plate senescence. In one study, when children with growth impairment due to celiac disease were placed on a gluten-free diet, the children's linear growth rate exceeded the normal for chronological age, indicating catch-up growth [14]. However, the growth pattern was normal for a child of younger age. Specifically, the subsequent growth rate matched the normal pattern of growth expected based on the initial bone age or height age. Because linear growth reflects longitudinal bone growth at the growth plate, the data imply that the growth plate function was appropriate for a younger child, consistent with the delayed senescence hypothesis.

In conclusion, catch-up growth at the growth plate appears to be due primarily to a local mechanism intrinsic to the growth plate rather than a systemic mechanism and can be explained, at least in part, by a delay in growth plate senescence.

Catch-up growth occurs not only in bone length but also in the mass of non-skeletal organs and the overall body mass [15, 16]. The catch-up growth in nonskeletal organs occurs also in terms of DNA content, indicating that accelerated cell proliferation makes an important contribution [15]. The mechanisms responsible for catch-up growth in nonskeletal organs appear to be analogous to the mechanisms in the growth plate, involving a delay in the loss of proliferative capacity.

In fetal and early postnatal mammalian life, cell proliferation is rapid, not only in the growth plate, but also in many nonskeletal organs. This rapid proliferation slows with age, primarily because of a decrease in the growth fraction (fraction of cells remaining in the cell-cycle) [17]. In both the growth plate and in nonskeletal organs, this decline in proliferation appears to be due to local rather than systemic mechanisms as evidenced by transplantation experiments between animals of different ages.

When juvenile organs, including the growth plate [18, 19], intestine [20, 21], kidney [22], and heart [23], are transplanted into older recipients they continue to grow rapidly, suggesting that growth deceleration is an intrinsic property of the organ.

Recent evidence suggests that cell proliferation is suppressed with age because of a complex growth-limiting genetic program that occurs during juvenile life in multiple tissues [24, 25]. This common program involves the downregulation with age of a large set of growth-promoting genes, including transcription factors like Plagl1, Ezh2 and Mycn, and extracellular growth factors like Mdk, Ptn and Igf2 [24, 25].

Importantly, this juvenile multiorgan genetic program appears to be driven not by time, but by growth. Thus, growth-inhibiting conditions slow the progression of the genetic program and thereby conserve future growth potential [24]. This concept is supported by studies in rats using a tryptophan-deficient diet or hypothyroidism to slow growth. After the period of growth inhibition, mRNA analysis indicated that the growth-limiting genetic program was delayed [25]. The period of growth inhibition due to tryptophan deficiency also appeared to delay the decline in proliferation rate in kidney and lung. Thus, after the animals had been returned to a normal diet, the proliferation rate in liver, kidney and lung was greater than in control animals. Taken together these data suggest that growth inhibition slows progression of the growth-limiting genetic program and thus delays the loss of proliferative capacity, allowing for subsequent catch-up growth.

After a period of growth inhibition, catch-up growth occurs, both in terms of body length, which reflects growth plate chondrocyte proliferation, and in terms of organ mass, which reflects proliferation in various nonskeletal tissues. Recent evidence suggests that catch-up growth in both the growth plate and in nonskeletal tissues occurs, at least in part, because growth-inhibiting conditions slow the physiological mechanisms that normally cause body growth to decelerate with age and cease. Therefore, if the growth-inhibiting condition resolves, the normal growth-limiting mechanisms are less advanced than normal, allowing for more rapid and more prolonged subsequent growth.

1.
Prader A, Tanner JM, von Harnack G: Catch-up growth following illness or starvation. An example of developmental canalization in man. J Pediatr 1963;62:646-659
2.
Boersma B, Wit JM: Catch-up growth. Endocr Rev 1997;18:646-661
3.
Wuelling M, Vortkamp A: Chondrocyte proliferation and differentiation. Endocr Dev 2011;21:1-11
4.
Abad V, Meyers JL, Weise M, Gafni RI, Barnes KM, Nilsson O, et al: The role of the resting zone in growth plate chondrogenesis. Endocrinology 2002;143:1851-1857
5.
van der Eerden BC, Karperien M, Wit JM: Systemic and local regulation of the growth plate. Endocr Rev 2003;24:782-801
6.
Bauer H: Nephrotic syndrome and body growth. Helv Paediatr Acta 1954;9:127-134
7.
Tanner JM: Regulation of growth in size in mammals. Nature 1963;199:845-850
8.
Baron J, Klein KO, Colli MJ, Yanovski JA, Novosad JA, Bacher JD, et al: Catch-up growth after gluco-corticoid excess: a mechanism intrinsic to the growth plate. Endocrinology 1994;135:1367-1371
9.
Marino R, Hegde A, Barnes KM, Schrier L, Emons JA, Nilsson O, et al: Catch-up growth after hypothyroidism is caused by delayed growth plate senescence. Endocrinology 2008;149:1820-1828
10.
Forcinito P, Andrade AC, Finkielstain GP, Baron J, Nilsson O, Lui JC: Growth-inhibiting conditions slow growth plate senescence. J Endocrinol 2011;208:59-67
11.
Walker KV, Kember NF: Cell kinetics of growth cartilage in the rat tibia. I. Measurements in young male rats. Cell Tissue Kinet 1972;5:401-408
12.
Walker KV, Kember NF: Cell kinetics of growth cartilage in the rat tibia. II. Measurements during ageing. Cell Tissue Kinet 1972;5:409-419
13.
Gafni RI, Weise M, Robrecht DT, Meyers JL, Barnes KM, De-Levi S, et al: Catch-up growth is associated with delayed senescence of the growth plate in rabbits. Pediatr Res 2001;50:618-623
14.
Emons JA, Boersma B, Baron J, Wit JM: Catch-up growth: testing the hypothesis of delayed growth plate senescence in humans. J Pediatr 2005;147:843-846
15.
Sant'Anna G, Mortola JP: Inter-organ unevenness and catch-up growth in rats. Growth Dev Aging 2003;67:27-46
16.
Meisami E: Complete recovery of growth deficits after reversal of PTU-induced postnatal hypothyroidism in the female rat: a model for catch-up growth. Life Sci 1984;34:1487-1496
17.
Chang M, Parker EA, Muller TJ, Haenen C, Mistry M, Finkielstain GP, et al: Changes in cell-cycle kinetics responsible for limiting somatic growth in mice. Pediatr Res 2008;64:240-245
18.
Stevens DG, Boyer MI, Bowen CV: Transplantation of epiphyseal plate allografts between animals of different ages. J Pediatr Orthop 1999;19:398-403
19.
Glickman AM, Yang JP, Stevens DG, Bowen CV: Epiphyseal plate transplantation between sites of different growth potential. J Pediatr Orthop 2000;20:289-295
20.
Cooke PS, Yonemura CU, Russell SM, Nicoll CS: Growth and differentiation of fetal rat intestine transplants: dependence on insulin and growth hormone. Biol Neonate 1986;49:211-218
21.
Montgomery RK, Sybicki MA, Grand RJ: Autonomous biochemical and morphological differentiation in fetal rat intestine transplanted at 17 and 20 days of gestation. Dev Biol 1981;87:76-84
22.
Pape L, Hoppe J, Becker T, Ehrich JH, Neipp M, Ahlenstiel T, et al: Superior long-term graft function and better growth of grafts in children receiving kidneys from paediatric compared with adult donors. Nephrol Dial Transplant 2006;21:2596-2600
23.
Crickmore MA, Mann RS: The control of size in animals: insights from selector genes. Bioessays 2008;30:843-853
24.
Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, et al: An extensive genetic program occurring during postnatal growth in multiple tissues. Endocrinology 2009;150:1791-1800
25.
Lui JC, Forcinito P, Chang M, Chen W, Barnes KM, Baron J: Coordinated postnatal down-regulation of multiple growth-promoting genes: evidence for a genetic program limiting organ growth. FASEB J 2010;24:3083-3092

Send Email

Recipient(s) will receive an email with a link to 'Nutrition and Growth > 100 - 104: Catch-Up Growth: Cellular and Molecular Mechanisms' and will not need an account to access the content.

Subject: Nutrition and Growth > 100 - 104: Catch-Up Growth: Cellular and Molecular Mechanisms

(Optional message may have a maximum of 1000 characters.)

×
Close Modal

or Create an Account

Close Modal
Close Modal