Somatomedin-binding proteins

Somatomedins are unusual in that unlike most polypeptide hormones they circulate in association with specific binding proteins [51,52]. At least two such proteins are found in blood plasma, with molecular weights of approx. 40-60000 and 150000. The relationship between these has not been determined, though their partial purification has been reported. The function of these binding proteins is not fully understood, though they appear to greatly extend the half-life (tm) of somatomedins - labelled somatomedin injected into animals has a tm of only about 10 min, whereas in association with binding protein tm appears to be about 3 h. 

In several laboratories it has been shown that normal liver and liver-derived cell lines in tissue culture release somatomedin binding proteins into the surrounding medium. In the rat, primary hepatocyte cultures (S22, S28), liver explants (B25) and isolated perfused liver (S9, S21) produce a protein of molecular mass 40-50,000. A binding species of similar size is released by the BRL 3A2 cell line (M24). Whereas somatomedin peptides could also be detected in all of these studies, human hepatoma (M22) and mammary carcinoma (B20) cell lines have been described which release the 40-50,000 molecular mass binding protein without any detectable low-molecular-mass somatomedins. Human amniotic fluid also contains a binding species of similar size (C8, D20) but, contrary to an original report that there was no detectable somatomedin (C8), it appears that both IGF-I and -II are also present (M14). 

000-molecular-mass form is converted to the larger species is unknown, although it may involve combination with an acid-labile subunit (see Section 

Presumably the conversion takes place at some extrahepatic site, unless it is assumed that perfusion and tissue culture media lack some components which the liver requires to make the conversion itself The exact nature of such a factor, and whether glycosylation or another posttranslational modification is involved, remain intriguing questions. 

Treatment of normal serum with acid, in addition to releasing somatomedins from their macromolecular complexes, also has the effect of reducing 

000 molecular mass). An additional, smaller binding protein, of Stokes radius 28.5 A (i.e., 40-50,000 molecular mass), was incapable of combining with the acid-labile protein to form the large complex. These data were interpreted as indicating that the high-molecular-mass binding complex contains at least two subunits, one of which is acid labile. 

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Daughaday WH, Kapadia M, Mariz I Serum somatomedin binding proteins physiologic significance and interference in radioligand assay./. Lab. Clin. Med. (1987) 109 355-363. 

GH may also stimulate production of at least some of the somatomedin-binding proteins. Production of binding proteins by hepatocytes in vitro has been demonstrated [60,61,64], as has its stimulation by GH. The 150K binding protein appears to be controlled by GH but not the 50K protein. 

Blum W, Ranke M, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR. A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin binding protein Its use for diagnosis of GH deficiency J Clin Endocrinol Metab 1990 70 1292-8. 

C17. Cohen, D. A., and Blethen, S. L., Somatomedin binding proteins in CH-deficient children with normal plasma somatomedin levels. J. Clin. Endocrinol. Metab. 56, 461-466 (1983). 

H20. Hintz, R. L., Liu, F., Rosenfeld, R. G., and Kemp, S. F., Plasma somatomedin-binding proteins in hypopituitarism Changes during growth hormone therapy. /. CUn. Endocrinol. Metab. 53, 100-104 (1981). 

M20. Morris, D. H., and Schalch, D. S., Structure of somatomedin-binding protein Alkaline pH-induced dissociation of an acid-stable 60,000 molecular weight complex into smaller components. Endocrinology (Baltimore) 111, 801-805 (1982). 

M24. Moses, A. C., Nissley, S. P., Passamani, J., and White, B. M., Further characterization of CH-dependent somatomedin-binding protein in rat serum and demonstration of somatomedin-binding protein produced by rat liver cells in culture. Endocrinology (Baltimore) 104, 536-546 (1979). 

The specific effects of GH on induction of somatomedin C (and its binding proteins) can be readily interpreted in terms of overall effects on somatic growth. The hormone also has effects on the production of other specific proteins, although here the connection with growth is less apparent. 

LBM includes skeletal muscle, somatic protein, and functional proteins such as circulating proteins and the visceral proteins. Biochemically, LBM can be assessed by measuring the serum visceral proteins, albumin (ALB), transferrin (TFN), and prealbumin (thyroxine-binding prealbumin or transthyretin). Other serum proteins, such as retinol-binding protein, flbronectin (an opsonic protein), and somatomedin-C (insulin-like growth factor-1), that have a very short half-life (less than 12 to 24 hours), have been suggested as... 

Consistent wdth a major role of the liver in maintaining normal somatomedin levels in the circulation, low levels of somatomedin-A activity have been found in unextracted plasma of patients with cirrhosis of the liver and chronic hepatitis (S14, T5). Significant correlations were seen between somatomedin-A and albumin, cholinesterase, and other indicators of liver function (T5). The decrease measured in this RRA appears to be due to low levels of both somatomedins and binding protein, since Zapf et al. (Z5) have shown an 89% decrease in immunoreactive IGF-I, a 74% decrease in total IGF by protein binding assay (which preferentially measures IGF-II), and a 57% decrease in specific binding of somatomedin tracer to stripped serum, in patients with cirrhosis. 

How are they delivered to cells Free somatomedins are not detectable in the circulation, but the extreme sensitivity of some cells to small amounts of the peptides leaves open the possibility that very low concentrations of unbound peptide might be responsible for major biological eflfects. If this is not the case, how does the binding protein complex release the growth factors at their target cells Where is the 150,000-molecular-mass complex produced, and what is its relationship to the various 40-60,000 molecular mass species ... 

B17. Baxter, R. C., Martin, J. L., and Handelsman, D. )., Identification of human semen insulin-like growth foctor-I/somatomedin-C immunoreactivity and binding protein. Acta Endocrinol. (Copenhagen) 106, 420-427 (1984). 

B18. Baxter, R. C., Zaltsman, Z., and Turtle, J. R., Immunoreactive somatomedin-C/insulin-like growth iactor-I and its binding protein in human milk. J. CUn. Ettdocrinol. Metab. 58, 955-959 (1984). 

D13. D Ercole, A. J., and Wilkins, J. R., Affinity labeled somatomedin-C binding proteins in rat sera. Endocrinology (Baltimore) 114, 1141-1144 (1984). 

Furlanetto, R. W., The somatomedin C binding protein Evidence for a heterologous subunit structure. J. CUn. Endocrinol. Metab. 51, 12-19 (1980). 

Spencer, E. M., Synthesis by cultured hepatocytes of somatomedin and its binding protein. FEBS Lett. 99, 157-161 (1979). 

Ginsberg, B. H., Kahn, C. R., Roth, J., Megyesi, K., and Baumann, G., 1979, Identification and high yield purification of insulin-like growth factors (nonsuppressible insulin-like activities and somatomedins) from human plasma by use of endogenous binding proteins, J. Clin. Endocrinol. Metab. 48 43. 

In laboratories which use an NSILA bioassay, however, somatomedin activity has been expressed in units of insulinlike activity, generally p,U/ml, a convention which has to some extent continued as radioligand assays were introduced. Expressed in these units, normal human samples have a mean value of 350 66 pU/ml by competitive protein-binding assay (Z4). In the same laboratory, a mean normal value ( SD) of 148 45 ng/ml was determined by IGF-I RIA (Z5). The close correspondence between reference values obtained by RIA in different laboratories, when expressed as ng/ml of SM-C or IGF-I, suggests that mass units, if uniformly adopted, would allow better comparison of results. With the increasing availability of highly pu-... 

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