Aluminum posttranscriptional regulation of parathyroid hormone synthesis: a role for the calcium-sensing receptor.
BACKGROUND
Calcium regulates parathyroid hormone (PTH) gene expression by a posttranscriptional mechanism, as well as parathyroid gland growth through the activation of the calcium-sensing receptor. Aluminum decreases both parathyroid cell proliferation and PTH levels by an unknown mechanism.


METHODS
To investigate the possible role of calcium-sensing receptor in the aluminum-induced PTH inhibition we used human embryonic kidney (HEK-293) cells transiently transfected with the human calcium-sensing receptor. We used a parathyroid gland tissue culture model to investigate whether the effect of aluminum in PTH mRNA was a transcriptional mechanism and also its possible role in calcium-sensing receptor expression.


RESULTS
We found that Al activated the calcium-sensing receptor with higher efficiency than calcium, its biologic ligand. Aluminum inhibited PTH gene expression by a posttranscriptional mechanism, but only when low calcium is present in the medium. Finally, we found that aluminum is also able to decrease calcium-sensing receptor mRNA levels by a posttranscriptional mechanism; however, no effect was observed on calcium-sensing receptor protein.


CONCLUSIONS
These findings indicate that aluminum impairs parathyroid function through a calcium-like mechanism due to the lack of specificity of the calcium-sensing receptor. Additionally, aluminum decreases parathyroid calcium-sensing receptor mRNA levels, and the regulatory mechanism was posttranscriptional. These findings demonstrate for the first time a regulatory effect in the calcium-sensing receptor by one of its ligands.
González-Suárez
Ignacio
I
Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, Hospital Universitario Central de Asturias, Oviedo, Spain.
Alvarez-Hernández
Daniel
D
Carrillo-López
Natalia
N
Naves-Díaz
Manuel
M
Luis Fernández-Martín
José
J
Cannata-Andía
Jorge B
JB
D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies; D001252:Astringents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D008297:Male; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010281:Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D017607:Aluminum Compounds; D000906:Antibodies; D001252:Astringents; D002712:Chlorides; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D000077410:Aluminum Chloride