Abstract: TH-PO533
Possible Clinical Relevance of Growth Hormone-Stimulated α-Klotho Upregulation
Session Information
- Bone and Mineral Metabolism: Basic
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Sato, Tetsuhiko, Nagoya Daini Red Cross Hospital, Nagoya, Aichi, Japan
- Koike, Megumi, University of Tokushima Graduate School, Tokushima, Japan
- Segawa, Hiroko, University of Tokushima Graduate School, Tokushima, Japan
- Miyamoto, Ken-ichi, University of Tokushima Graduate School, Tokushima, Japan
- Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, Kanagawa, Japan
Background
An aging suppressor protein, α-Klotho, known as a key factor for calcium-phosphorus homeostasis, is believed to have diverse physiological properties, because its global genetic deletion animal model shows short-stature and multi-organ dysfunction, resulting in early death. Interestingly, recent studies suggest that pituitary function plays an intriguing role, because growth hormone (GH)-producing pituitary adenoma significantly upregulates systemic α-Klotho levels. In end stage kidney disease (ESKD), growth spurt of pediatric patients is disturbed and often GH-resistant, whereas adult bone mineral disorder remains an unsolved clinical entity.
Methods
To elucidate the magnitude of GH/α-Klotho axis on both pituitary and bone-mineral reaction, we performed experiments involving GH administration to wild-type mice and adenine-induced kidney failure mice. GH was intraperitoneally given to 4-week-old male mice (C57BL/6J). We examined α-klotho mRNA expression, quantified by RT-PCR, in the pituitary gland and cancellous bones of mice with or without kidney dysfunction. Additionally, we performed immunohistochemistry (IHC) analysis of α-Klotho expression, surgically obtained from patients with pituitary adenomas.
Results
Exogenous GH increased α-klotho mRNA levels in the pituitary, and more robustly in cancellous bones. Strikingly, kidney failure cancelled GH-induced α-klotho expression in the pituitary and trabecular bones. Unexpectedly, GH administration induced modest α-klotho mRNA expression and markedly increased urinary excretion of soluble α-Klotho in wild-type mice, suggesting that GH triggers systemic circulation of α-Klotho in the bloodstream. IHC results indicated that pituitary GH-producing adenomas expressed α-Klotho more strongly than other (ACTH-producing, TSH-producing, or non-functioning) adenomas.
Conclusion
Established chronic kidney disease causes bone mineral disease, possibly by disrupting GH/α-Klotho axis. GH supplementation alone fails to catch up bone growth in juvenile patients with ESKD partly because of disrupted GH-triggered α-Klotho upregulation. Its stimulation might be a treatment option for patients with refractory bone and mineral disorders in ESKD. Organ-specific activation of GH/α-Klotho pathway might be a therapeutic target for restoring each organ function, leading to ideal organ rejuvenation and longevity.
Funding
- Private Foundation Support