Unbound (bioavailable) IGF1 enhances somatic growth

Abstract

SUMMARYUnderstanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or ‘free IGF1’. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

Insulin-Like Growth Factor 1 Physiology

“…41–44 Introduction of these 2 mutations to mouse models via knockin resulted in enhanced somatic growth, which was attributed to increased IGF-1 bioavailability in tissues. 45,46 Together, studies of IGFBP knockout and the Des/R3 knockin mouse models support the notion that IGFBPs serve as reservoirs that release and control IGF action in tissues.…”

Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models

“…The first, a knock-in mouse of Des-IGF-1 (KID), which express an IGF-1 peptide with a three amino acid truncation at the N-terminus; and the second, a knock-in mouse of R3-IGF-1 (KIR), which express an IGF-1 where the glutamine at position 3 was substituted with arginine (R) (72). Both IGF-1 mutants have several times lower affinity to IGFBP-3 and significant reductions in binding to all other IGFBPs.…”

Past, Present, and Future in the Relationship between Growth Retardation and the IGF System: Excerpts from the Cesar Bergada Lecture Given during the SLEP 2015 Annual Meeting

“…There is, for studying the reduced actions of binding proteins, a mouse model available [20]. On the other hand, recent data concerning the pregnancy-associated plasma protein A2 (PAPP-A2) mutations in children [21] increased our knowledge on the increased action of IGFBP-3 and IGFBP-5.…”

“…This increased growth is not harmonic, not proportionate, i.e. expressing organ weight as percent of body weight, KID mice showed reductions in some organs: liver (14%), gonadal fat (50%), quadriceps muscle (46%), mammary gland (39%), and increments in others: pancreas (55%), kidney (24%), and uterus and ovaries (83%) [20]. …”