The negative effect of dexamethasone on calcium-processing gene expressions is associated with a
Man-Hee Kim1, Geun-Shik Lee, Eui-Man Jung
1Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 361-763 Republic of Korea.
Aims:
Although dexamethasone (Dex) is used widely as an anti-inflammatory and immunosuppressive drug, Dex appears to have severe side-effects, including osteoporosis. This study determined the effects of Dex on duodenal and renal expressions of the calcium-processing genes transient receptor potential cation channel, subfamily V, member 5/6 (TRPV5/6), calbindin-D9k/-D28k (CaBP-9k/28k), Na+/Ca2+ exchanger 1 (NCX1), and plasma membrane Ca(2+)-ATPase (PMCA) 1b.
Main Methods:
Mice were injected subcutaneously with Dex for 1 or 5 days. The mRNA and protein expression levels of these calcium-processing genes were measured by real-time PCR and immunohistochemistry/immunoblot analysis, respectively. In addition, serum parathyroid hormone (PTH) levels were measured following Dex treatments.
Key Findings:
Treatment with Dex for 24 h resulted in the inductions of duodenal TRPV6, CaBP-9k and PMCA1b transcripts and renal TRPV5, CaBP-9k, and NCX1 transcripts, while it reduced the transcription of renal TRPV6. Although the expressional changes were weak, duodenal expressions of glucocorticoid receptor (GR), the vitamin D receptor (VDR), and renal expressions of the parathyroid hormone receptor (PTHR) and VDR were increased following 24 h treatment with Dex. A five-day treatment with Dex reduced the transcriptional levels of duodenal TRPV6 and CaBP-9k by 60%. Transcripts for VDR and GR in the duodenum increased marginally.
Significance:
These results suggest that the expressions of TRPV6 and CaBP-9k in the duodenum appear to be a major regulatory target for glucocorticoids (GCs), and may be involved in the negative regulation of calcium absorption in GC-induced osteoporosis (GIO). The transcriptional regulation of TRPV6 and CaBP-9k in the duodenum seems complex given that there is an increase at 1-day treatment followed by a decrease at 5-day treatment.
Insights
Dexamethasone (Dex) alters calcium processing genes in the duodenum and kidneys. Short-term Dex increases some gene expressions, while long-term use significantly reduces duodenal TRPV6 and CaBP-9k, potentially contributing to glucocorticoid-induced osteoporosis.
Area of Science:
- Endocrinology
- Molecular Biology
- Nephrology
Background:
- Dexamethasone (Dex) is a widely used anti-inflammatory and immunosuppressive drug.
- Dex use is associated with severe side effects, notably osteoporosis.
- Calcium processing gene regulation is crucial for maintaining calcium homeostasis.
Purpose of the Study:
- To investigate the effects of Dex on the expression of key calcium-processing genes in the duodenum and kidneys.
- To elucidate the role of these genes in the development of glucocorticoid-induced osteoporosis (GIO).
Main Methods:
- Mice were administered Dex subcutaneously for 1 or 5 days.
- Gene expression (mRNA and protein) of calcium-processing genes (TRPV5/6, CaBP-9k/28k, NCX1, PMCA1b) was analyzed using real-time PCR and immunohistochemistry/immunoblotting.
- Serum parathyroid hormone (PTH) levels were measured.
Main Results:
- Short-term (24h) Dex treatment induced duodenal TRPV6, CaBP-9k, PMCA1b, and renal TRPV5, CaBP-9k, NCX1, while downregulating renal TRPV6.
- Long-term (5-day) Dex treatment significantly reduced duodenal TRPV6 and CaBP-9k expression by 60%.
- Expressions of glucocorticoid receptor (GR), vitamin D receptor (VDR), and parathyroid hormone receptor (PTHR) were modulated by Dex treatment.
Conclusions:
- Duodenal TRPV6 and CaBP-9k expression are likely key targets for glucocorticoid regulation.
- These genes may play a significant role in the negative calcium absorption observed in GIO.
- The complex transcriptional regulation of duodenal TRPV6 and CaBP-9k by Dex, with differing effects at 1 versus 5 days, warrants further investigation.
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