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Cited by 53Growth Hormone and Insulin-like Growth FactorsConnective tissue disorders researchHuman Health and Disease

Insulin-like growth factors and skeletal growth: possibilities for therapeutic interventions

Van Wyk, Judson J., Smith, Eric P.·1999·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.84.12.6201
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Abstract

In this, her last issue as editor-in-chief of JCEM, Dr. Maria New has invited some of her colleagues in pediatric endocrinology to contribute short commentaries on issues of current interest. It is a pleasure to honor Dr. New on this occasion, both for her leadership in taking our journal to a new level of excellence and for her many scientific contributions that have enhanced our understanding and treatment of adrenal disorders. The central focus of pediatric endocrinology has been the hormonal control of growth and development, and in recent decades it has been possible to correlate the serum concentrations of nearly every known hormone with each phase of normal growth and with most types of aberrant growth. The insulin-like growth factors (IGFs) or somatomedins, as they are frequently called, have been an important focus of pediatric endocrinologists because of their pivotal role in skeletal growth. The present essay addresses the roles of these peptides in the growth of the skeleton and considers how we might take advantage of their many actions for therapeutic purposes. The two known somatomedins, IGF-I and IGF-II, are structurally homologous to proinsulin. They were initially identified on the basis of three unique properties: their mediation of the skeletal growth-promoting actions of GH, their mitogenic properties, and their mimicry of the actions of insulin. These peptides were isolated in Zurich by Rinderknecht and Humbel on the basis of their insulin-like activity, but were renamed IGF-I and IGF-II when it became apparent that their growth-promoting properties were more important than their insulin-like activities (1). Somatomedin C was isolated in Chapel Hill from human blood fractions by Van Wyk et al. guided by assays based on the stimulation of proteoglycan and DNA synthesis in cartilage as suggested by William Daughaday. Somatomedin C was found on sequence analysis to be identical to IGF-I as reported by the Zurich group (2). As no peptide comparable to IGF-II was isolated under the somatomedin rubric, it is now conventional to use IGF-I and IGF-II when referring to the specific peptides and the term somatomedins or IGFs when referring to these peptides generically (3). The IGFs are more primitive hormones than insulin and have a much broader spectrum of action. Insulin presumably evolved from the IGFs to fulfill a more specialized function when the need arose to store energy during periods of fasting. The ancestral relationship of insulin to IGFs to insulin is similar to that of PTH to PTH-related protein (PTHrP), with PTHrP having a more ubiquitous spectrum of activities than PTH. Both of the somatomedins are developmentally regulated and subject to precise tissue-specific expression. Methods for the quantitation of IGF-I were developed before comparable methods became available for IGF-II (4, 5), and to this day much less is known about the physiological roles of IGF-II than those of IGF-I. Blood levels of IGF-II are considerably higher than those of IGF-I, and the concentrations of IGF-II in extracts of skeletal tissue are higher than those of IGF-I. Blood levels of IGF-I are more stringently regulated by GH and nutritional factors than are those of IGF-II, but IGF-II is more insulin like than IGF-I. The idea has been perpetuated that IGF-II is the fetal hormone and IGF-I is the somatomedin of postnatal life. It is now clear, however, that both IGF-I and IGF-II are important for normal fetal growth and that both have distinctive functions postnatally. Most of the IGF-I circulating in blood comes from the liver, where the expression of the IGF-I gene is regulated by GH (6). The IGFs are also produced in peripheral tissues, where the expression of their genes is regulated by many hormones. IGFs are required for the proliferation of most cell types, and they promote cell survival by inhibiting programmed cell death (7). They also regulate a vast number of highly differentiated cell functions. The nature of the responses to IGFs is dependent on physiological circumstance. It is pertinent to the role of IGFs in skeletal growth that sparsely plated chondrocytes respond to IGF-I with increased DNA synthesis, but not with increased sulfate incorporation into proteoglycans. On the other hand, when the same cells reach confluence, IGF-I stimulates matrix synthesis but has no effect on DNA synthesis. Such observations imply that IGFs may act as both a mitogen in the proliferative zone and a stimulant of proteoglycan synthesis in the hypertropic zones of the growth plate, with the specific effect being dependant on the cellular and hormonal environments. The biological importance of the somatomedins is often underestimated because their effects, compared with those of other growth factors, are often weak or difficult to demonstrate. This is because the IGFs characteristically exercise a permissive or modulating role on biological processes rather than serving as the primary agonist. This was illustr

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Authors
Van Wyk, J. J., & Smith, E. P.
Affiliations
University of Cincinnati (US)
ORCID
Smith, Eric P.
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1999-12
Volume
84
Issue
12
Pages
4349-4354
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.84.12.6201
OpenAlex
W2102201405
Cited by
53
References
59
Citations by year
2024: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 2
FWCI
1.62
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Human Health and Disease
Keywords
insulin-like growth factor, insulin-like growth factor I, insulin-like growth factor II, skeletal development, growth hormone, therapeutic interventions, insulin-like activity, growth disorders, PTH-related protein, growth hormone deficiency, growth hormone excess, growth hormone insensitivity
MeSH terms
Animals, Bone Development, Humans, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Receptor, IGF Type 1, Receptor, IGF Type 2, Mice, Knockout, Insulin-Like Growth Factor Binding Proteins, Mice

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