Deficiency in RECK protein disrupts GH/IGF-1 axis, reducing growth hormone and plasma IGF-1 in mice
Background
The Reck gene, a known tumor suppressor, encodes a membrane-anchored protease regulator that is crucial for embryonic development. However, its specific physiological roles in postnatal life have remained largely unclear. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is a fundamental hormonal system that regulates somatic growth and metabolism. It involves the pituitary gland producing growth hormone (GH), which then stimulates the liver to produce IGF-1. Understanding the regulators of this intricate system is key to addressing growth disorders. This study investigates the unexpected, abundant expression of Reck in GH-producing cells (somatotrophs) of the anterior pituitary, suggesting it might play a previously unknown regulatory role in this vital axis.
Study Design
Researchers studied two viable Reck mutant mouse models. The first model had constitutionally reduced RECK expression (Hypo mice). The second was an inducible knockout model (iKO mice) where Reck deficiency was induced via tamoxifen treatment starting 10 days after birth. The scientists analyzed phenotypes including body size and plasma IGF-1 levels. They then characterized several key molecules in the anterior pituitary gland and liver using immunoreactivity assays to measure protein levels and mRNA analysis to measure gene expression of receptors like GHSR, GHRHR, and GHR.
Results
Both mutant mouse models (Hypo and iKO) exhibited common phenotypes, including significant decreases in body size and reduced plasma levels of IGF-1. In the tamoxifen-treated iKO mice, immunoreactivity for growth hormone (GH) in the anterior pituitary was greatly reduced. Paradoxically, while the protein levels for key GH-stimulating receptors (GHSR and GHRHR) were decreased in these mice, their corresponding mRNA levels were increased. This pattern of decreased protein with increased mRNA was also observed for GHSR in the Hypo mice.
Furthermore, a similar discrepancy was found in the liver of Hypo mice, where growth hormone receptor (
GHR) protein immunoreactivity was reduced while itsmRNAwas concurrently increased. These findings consistently point to a post-transcriptional disruption in the GH signaling pathway when RECK function is compromised.
Key Findings
- RECK protein is abundantly expressed in growth hormone (GH)-producing somatotrophs in the mouse anterior pituitary.
- Mice with reduced or deficient RECK (Hypo and iKO models) exhibit decreased body size and lower plasma IGF-1 levels.
- In iKO mice, GH protein was greatly reduced, while GHSR and GHRHR receptor proteins decreased but their mRNAs increased.
- In Hypo mice, GHSR protein in the pituitary was decreased while its mRNA increased.
- In the liver of Hypo mice, GHR protein was decreased while its mRNA was increased, indicating a systemic effect.
Why It Matters
This research reveals a novel and critical role for the RECK protein in maintaining the stability and proper function of the GH/IGF-1 axis. The observed discordance between receptor protein levels and their mRNA suggests RECK may be essential for the post-transcriptional regulation, stability, or processing of key receptors like GHSR and GHR. For individuals exploring growth hormone optimization, this highlights a potential underlying factor—RECK function—that could influence the efficacy of GH secretagogues or exogenous GH. Disruptions in RECK expression could theoretically blunt the response to GH-related therapies. While this is preclinical animal research, it opens a new avenue for investigating growth disorders and metabolic issues, suggesting that modulating RECK or its downstream targets could be a future therapeutic strategy. Further studies are needed to see if this mechanism is relevant in humans.
