Functional Antagonism between Endogenous Mouse Growth Hormone (GH) and a GH Analog Results in Dwarf Transgenic Mice^*

Abstract

A dwarf transgenic mouse (DTM) line has been established in which mice express relatively high levels of a mutated bovine (b) GH gene. This bGH analog binds to mouse liver membrane preparations with an affinity similar to that of wild-type bGH. The mean growth ratio of these mice is approximately 0.7 relative to that of their nontransgenic littermates. Serum insulin-like growth factor-I (IGF-I) levels of DTM were found to be approximately half those in nontransgenic littermates. Liver GH receptor levels were up-regulated in DTM or wild-type bGH transgenic mice. Pituitary GH levels were negatively correlated with serum IGF-I concentrations. Wild-type bGH transgenic mice contain relatively high serum IGF-I and low pituitary GH levels, whereas DTM possess low serum IGF-I and high pituitary GH levels. The decrease in serum IGF-I resulting from the interaction between the bGH analog, the endogenous mouse GH, and GH receptor(s) apparently leads to a dwarf phenotype. These data suggest that this bGH analog has uncoupled GH ligand-receptor binding from IGF-I production and acts as a functional antagonist to the action of endogenous mGH.

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…Taking together these observations we can suggest that local manipulation of JAK-STAT activation can be a very perspective therapeutic approach for managing of cholangiocarcinoma at different stages of its progression. Recent advances in development of hormonal and cytokine antagonists (recombinant proteins for Prl and GH and peptide for IL-6 [145][146][147] ) give us an efficient tool for this treatment. Since synthetic specific inhibitors of JAK and other tyrosine kinases are intensively developed, we could suggest their efficient application for managing of cholangiocarinoma in addition to antagonists.…”

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

“…A series of highly specific antagonists of the GH action has recently been developed for the potential therapeutic use in various pathophysiological conditions, including diabetes. Initially it was shown that alteration of single amino acids in the third a-helix of bovine (b)GH (residues 109±126) results in a GH antagonist [68,69]. In vitro experiments showed that this new group of GH antagonists binds to the GH receptor with the same affinity as native GH but in vivo a phenotypic dwarf animal characterized by low circulating IGF-I concentrations and a proportional body composition develops when the GH antagonist is expressed in transgenic (TG) mice [68,69].…”

“…Initially it was shown that alteration of single amino acids in the third a-helix of bovine (b)GH (residues 109±126) results in a GH antagonist [68,69]. In vitro experiments showed that this new group of GH antagonists binds to the GH receptor with the same affinity as native GH but in vivo a phenotypic dwarf animal characterized by low circulating IGF-I concentrations and a proportional body composition develops when the GH antagonist is expressed in transgenic (TG) mice [68,69]. Studies in long-term diabetic GH antagonist TG mice, that express the GH antagonist (bGH-G119R or hGH-G120R), have shown that these animals are protected against development of diabetic renal changes [70,71].…”

Growth Hormone and Translational Research: From the 'Bench' to the 'Bedside'

“…The transgene is a mutated bGH gene in which the codon for glycine at position 119 is replace by arginine or lysine (G119K) [51][52][53]. Expression of these two mutated GH transgenes surprisingly results in reduced GH action and was later found to be a classic receptor antagonist [54].…”