Molecular Forms of Serum Insulin-Like Growth Factor (IGF)-Binding Proteins in Man: Relationships with Growth Hormone and IGFs and Physiological Significance*

Abstract

Insulin-like growth factor-I (IGF-I) and IGF-II are associated in the blood with specific binding proteins (BPs), forming complexes that elute in gel filtration with estimated mol wt around 40 and 150 kD. The latter appears to be under GH control. Five molecular forms of BP (41.5, 38.5, 34, 30, and 24 kD) have been identified by Western blotting using 125I-labeled IGF. All five forms are present in the smaller complexes, but only the 41.5- and 38.5-kD forms are found in the larger complexes. In this study immunoblotting showed that the 41.5- and 38.5-kD forms were recognized by antibodies directed against the GH-dependent BP purified from human plasma, and the 30-kD form was recognized by antibodies directed against the BP purified from amniotic fluid. The 34- and 24-kD forms proved to be immunologically unrelated to the other three. In sera with large quantities of the 41.5- and 38.5-kD forms, an additional band was often observed immediately ahead of the migration front of the 30 kD band. This was recognized by the anti-GH-dependent BP antibody and probably corresponds to a degradation product of the 41.5- and 38.5-kD BPs. Serum 41.5- and 38.5-kD BPs have been found to be elevated in acromegaly, where GH hypersecretion causes increased IGF-I levels, and diminished in cases of genetic or idiopathic GH deficiency and defects of the GH receptor (Laron's syndrome), where both IGF-I and IGF-II are decreased, as well as in Pygmy adults and children who have isolated IGF-I deficiency. In all of these conditions, the proportions of the 34- and 30-kD forms were inversely related to those of the 41.5- and 38.5-forms. Under treatment, the BP profiles tended to return to normal. In cases of GH deficiency caused by a tumor, the BP profiles resembled those of hypopituitary or normal serum, depending on whether IGF levels were diminished or normal. It, therefore, seems that BP synthesis is coordinated with IGF-I synthesis and may not be directly GH dependent. The results of neutral pH gel filtration analysis of hypopituitary (idiopathic and tumoral) and normal sera point to a relationship between the levels of circulating IGFs and those of the 150-kD IGF-BP complex whose binding units are the 41.5- and 38.5-kD BPs. It, therefore, seems that the 150-kD complex controls the bioavailability of IGF-I and IGF-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis of insulinlike growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: Regulation by insulin, insulinlike growth factor, and growth hormone

“…In contrast to insulin and IGF-I, a response to GH was not observed. In view of altered IGFBP serum concentrations in states of GH excess or deficiency reported previously, 33,34 this latter observation supports the concept that GH acts indirectly on hepatic IGFBP biosynthesis, e.g., by increasing levels of insulin or IGF-I. A similar mechanism of GH regulatory action has been suggested by Camacho-Hubner et al, 35 demonstrating increased IGFBP-3 serum levels in GH-deficient mice overexpressing a transgene for IGF-I.…”

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

“…23,24 According to endocrinological assays, pygmy individuals have normal levels of GH but lower serum levels of IGF1, and exhibit an eightfold underexpression of the GHR gene as compared with the controls. 16,18,19 Therefore, the GHR and IGF1 genes represent good candidates to explain pygmies' short stature. We develop here a candidate-gene approach focusing on these two genes and on the signal transducers and activators of transcription STAT5A and STAT5B.…”

“…18 Small regions of the GHR and IGF1 genes have been previously tested for association with the stature of African pygmies with negative results. [18][19][20][21] A recent genome-wide study has identified regions in the genome that might be involved in the difference in stature observed between pygmies from Cameroon and their non-pygmy neighbors, although this signal was not significant. 22 Some of these regions contain genes linked to the GH-IGF1 signaling pathway.…”

Normal expression of type 1 insulin‐like growth factor receptor by human osteoarthritic chondrocytes with increased expression and synthesis of insulin‐like growth factor binding proteins

“…In general, each cell type secretes a distinct pattern of binding proteins and changes in their secretion are associated with changes in certain cell functions. In various pathologic states, the level of one or more of these IGFBP has been found to disrupt the normal metabolism through sequestration of the IGF (34,35).…”

“…For example, in human fibroblasts, both IGF-1 and transforming growth factor p demonstrated their ability to increase levels of IGFBP-3 and 4, and in the case of IGF-1, without influencing the transcript levels (35,543). In certain cell types, the intracellular level of CAMP also seemed to increase both the protein and the mRNA expressions of IGFBP-4 (42,56).…”