There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations

This two-volume treatise, the collected effort of more than 50 international experts, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. These substances are of universal importance in biology and medicine and are the basis of common language of intercellular communication.-The detailed description of each of the major peptide growth factors is the principal focus of these volumes. Essential information is provided on the primary structure, gene structure, gene regulation, cell surface receptors, biological activity, and potential therapeutic applications of each growth factor. The coordinate actions of sets of growth factors and their role in controlling fundamental processes that pertain to many different cells and tissues are also dealt with.-The peptides described here are of fundamental importance for understanding the behavior of all cells, and they will be of major importance in the practice of clinical medicine in the years to come.- These volumes will be of value to both researchers and clinicians in their pursuit and application of new knowledge in this promising area.

Peptide Growth Factors and Their Receptors

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1990.tb15595.x

Insulin-like growth factors I and II

Transforming growth factor-β (TGF-β) is generally acknowledged to be the cytokine with the broadest range of activities in repair of injured tissue, based both on the variety of cell types that produce and/or respond to it and on the spectrum of its cellular responses (Roberts and Sporn, 1990). TGF-β is released from degranulating platelets and secreted by all of the major cell types participating in the repair process, including lymphocytes, macrophages, endothelial cells, smooth muscle cells, epithelial cells, and fibroblasts (see Fig. 1). A unique feature of this molecule is that its autoinduction results in sustained expression at the site of a wound and extends the effectiveness of both the initial burst of endogenous TGF-β released upon injury and exogenous TGF-β that might be applied to a wound. The ability of TGF-β to improve and/or accelerate tissue repair has been studied extensively in a variety of animal models of both normal and impaired healing. A limited number of clinical trials are in progress, but it is anticipated that many new applications for TGF-β will ultimately be found, once problems with appropriate timing and formulation can be solved.

Transforming Growth Factor-β

Following the initial purification and characterization of transforming growth factor-β (TGF-β) as a homodimeric, 25-kDa peptide (Frolik et al. 1983; Assoian et al. 1983; Roberts et al. 1983a), there has been an exponential increase in knowledge relating to this molecule. The cloning of TGF-β1 and the resultant elucidation of its precursor structure (Derynck et al. 1985) have led to the identification of at least four other forms of TGF-β and the definition of a larger gene family comprising many other structurally related, but functionally distinct, regulatory proteins. The original narrow definition of TGF-β, in terms of induction of a transformed phenotype in mesenchymal cells (Moses et al. 1981; Roberts et al. 1981, 1983 b), has now been supplanted by the knowledge that this peptide affects many functions in nearly all cells. Immunohistochemical and in situ hybridization studies have identified in vivo sites of TGF-β action; its broad spectrum of cellular targets as well as its multifunctional actions suggest that it has a pivotal control function in many physiological and pathological processes. Elucidation of physiological mechanisms of activation of the latent forms of the TGF-βs and of regulation of expression of the TGF-βs and their receptors are important problems that must still be solved for better understanding of the action of the TGF-βs. In this chapter we summarize current knowledge of the chemistry and complex biology of the growing family of TGF-βs.

The Transforming Growth Factor-βs

Developmental regulation of insulin-like growth factor II mRNA in different rat tissues.

Somatomedins/insulin-like growth factors (Sm/IGFs) are present in blood and in extracts from multiple tissues of the human fetus and induce the proliferation of cultured human fetal cells. To identify the cellular location of immunoreactive Sm/IGF in human fetal tissues, we have performed immunocytochemistry in tissues from prostaglandin-induced human fetal abortuses of 12 to 20 wk in gestation. Every tissue studied except the cerebral cortex contains Sm/IGF immunoreactive cells. Cells staining positively include hepatocytes, hepatic hemopoietic cells, columnar epithelia of the pulmonary airways, intestine and kidney tubules, adrenal cortical cells, dermal cells, skeletal and cardiac muscle fibers, and pancreatic islet and acinar cells. Immunostaining was specific for Sm/IGFs, but because of the cross-reactivity of the antibodies it was not possible to determine whether the immunoreactivity represented Sm-C/IGF I, IGF II, or both. Liver contained the greatest proportion of immunoreactive cells, while the thymus and spleen had only a few immunostained cells. With the possible exception of dermal and some adrenal cortical cells, the immunoreactive cells do not appear to be the primary sites of Sm/IGF synthesis, because parallel in situ hybridization histochemical studies using Sm/IGF oligodeoxyribonucleotide probes show that Sm/IGF mRNAs are localized predominantly to fibroblasts and mesenchymal cells. Therefore the immunoreactive cells identified in this study may define sites of action of Sm/IGFs.

/pdf/identification-of-somatomedin-insulin-like-growth-factor-3fq9niky0q.pdf

Identification of somatomedin/insulin-like growth factor immunoreactive cells in the human fetus.

We investigated the influence of transforming growth factor-beta (TGF-beta) on DNA synthesis in human fetal fibroblasts, as measured by the incorporation of [3H]thymidine and cell replication. In serum-free medium, without additional peptide growth factors, TGF-beta had no action on thymidine incorporation. However, in the presence of 0.1% v/v fetal calf serum, TGF-beta exhibited a bi-functional action on the cells. A dose-dependent stimulation of [3H]thymidine incorporation, and an increase in cell number, occurred with fibroblasts established from fetuses under 50 g body weight, with a maximum stimulation seen at 1.25 ng/ml. For fibroblasts from fetuses of 100 g or greater body weight, TGF-beta caused a dose-related decrease in thymidine uptake with a maximal inhibition at 2.5 ng/ml, and a small decrease in cell number. When DNA synthesis was stimulated by the addition of somatomedin-C/insulin-like growth factor I, epidermal growth factor, or platelet-derived growth factor, their actions were potentiated by the presence of TGF-beta on cells derived from fetuses under 50 g body weight, but inhibited on cells obtained from the larger fetuses weighing more than 100 g. Similar results were found for changes in cell number in response to TGF-beta when stimulated by SM-C/IGF I. The ability of TGF-beta to modulate [3H] thymidine incorporation did not involve a change in the time required for growth-restricted cells to enter the S phase of the replication cycle. These data suggest that TGF-beta may exert either a growth-promoting or growth-inhibiting action on human fetal connective tissues in the presence of other peptide growth factors, which is dependent on fetal age and development.

Bi-functional action of transforming growth factor-β on DNA synthesis in early passage human fetal fibroblasts

We compared the abilities of human placental lactogen (hPL), somatomedin-C/insulin-like growth factor I (SM-C/IGF-I), multiplication-stimulating activity (MSA), and insulin to induce a rapid anabolic event, the uptake of the nonmetabolizable amino acid [3H[α-aminoisobutyric acid ([3H] AIB) or the more long term action of increasing [3H]thymidine incorporation, as a measure of DNAsynthesis, in isolated human fetal fibroblasts and myoblasts. Myoblasts were derived from skeletal muscle and fibroblasts from skin explants removed from human fetuses delivered between 12 and 19 weeks gestation after prostaglandin-induced abortion. Each of the four peptides caused a dose-dependent increase in [3H]AIB uptake by both fibroblasts and myoblasts, with mean half-maximal concentrations (ED50) ranging from 0.9–1.9 nM. The concentration of each peptide required to stimulate [3H] thymidine uptake was significantly greater, with the exception of insulin, which was inactive. For myoblast cultures, the meanED50 values were: h...

Regulation of Amino Acid Uptake and Deoxyribonucleic Acid Synthesis in Isolated Human Fetal Fibroblasts and Myoblasts: Effect of Human Placental Lactogen, Somatomedin-C, Multiplication-Stimulating Activity, and Insulin

The specific binding of human placental lactogen (hPL) and human GH (hGH) to particulate cell membranes from human fetal liver and skeletal muscle at 12-19 weeks gestation was examined. Fetal liver and muscle specifically bound [125I]hPL. This binding was inhibited by increasing concentrations of unlabeled hPL (half-maximal concentrations, 2.2 and 3.4 nmol/L, respectively). Scatchard analysis of the hepatic membrane binding revealed curvilinear plots with higher (Kd, 2.2 nmol/L) and lower (Kd, 24 nmol/L) affinity sites, while binding to muscle involved a single receptor class of Kd 5.6 nmol/L. The binding capacities for the two hepatic sites correlated positively with fetal body weight. [125I]hGH specifically bound to liver, but not muscle, with higher (Kd, 1.6 nmol/L) and lower (Kd, 8.6 nmol/L) affinity sites. [125I]PRL bound to hepatic membranes, but was preferentially displaced by hPL or hGH. Between 4 and 500 micrograms/L (mean, 82 micrograms/L, 3.8 nmol/L) hPL were present in fetal plasma. The findings identify distinct hPL receptors in human fetal liver and skeletal muscle and a hepatic hGH receptor in midgestation.

Placental Lactogen and Growth Hormone Receptors in Human Fetal Tissues: Relationship to Fetal Plasma Human Placental Lactogen Concentrations and Fetal Growth

A. J. Strain

Papers

Developmental regulation of insulin-like growth factor II mRNA in different rat tissues.

Identification of somatomedin/insulin-like growth factor immunoreactive cells in the human fetus.

Bi-functional action of transforming growth factor-β on DNA synthesis in early passage human fetal fibroblasts

Regulation of Amino Acid Uptake and Deoxyribonucleic Acid Synthesis in Isolated Human Fetal Fibroblasts and Myoblasts: Effect of Human Placental Lactogen, Somatomedin-C, Multiplication-Stimulating Activity, and Insulin

Placental Lactogen and Growth Hormone Receptors in Human Fetal Tissues: Relationship to Fetal Plasma Human Placental Lactogen Concentrations and Fetal Growth