Type I membrane klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism.
BACKGROUND
The type I membrane protein Klotho was recently shown to mediate PTH secretion in parathyroid cells in response to low extracellular calcium. In contrast, Klotho inhibits PTH secretion indirectly through the action of fibroblast growth factor-23. Abnormal Klotho expression in parathyroid disorders remains to be elucidated.


OBJECTIVE
The aim of the study was to determine: 1) Klotho expression in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT) compared to normal tissue; and 2) its relation to the serum calcium and PTH levels.


METHODS
Surgically removed parathyroid glands (n = 40) and four normal parathyroid tissue specimens were analyzed for Klotho mRNA and protein levels by quantitative real-time PCR and immunohistochemistry. In vitro effects of calcium on Klotho mRNA expression were studied in bovine parathyroid cells.


RESULTS
Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P < 0.001). Reduced Klotho protein expression was confirmed by immunohistochemistry. Klotho mRNA levels were inversely correlated to serum calcium (r = -0.97; P < 0.0001), and calcium dose-dependently decreased Klotho mRNA expression in normal parathyroid cells in vitro (P < 0.01). Serum calcium was the only significant marker of Klotho expression in multivariate analysis with calcium, phosphate, PTH, and adenoma weight as independent variables.


CONCLUSIONS
Parathyroid Klotho expression is decreased or undetectable in pHPT. We provide evidence that 1) serum calcium is strongly associated with parathyroid Klotho expression in pHPT; and 2) abnormal PTH secretion in hypercalcemic pHPT subjects is mediated by Klotho-independent mechanisms.
Björklund
Peyman
P
Department of Medical Sciences, Uppsala University Hospital, Ing.70, 3 tr, UAS, 75185 Uppsala, Sweden. tobias.larsson@medsci.uu.se.
Krajisnik
Tijana
T
Akerström
Göran
G
Westin
Gunnar
G
Larsson
Tobias E
TE
D000236:Adenoma / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002118:Calcium / Q000097:blood*; D002417:Cattle; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood; D010282:Parathyroid Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D008565:Membrane Proteins; D010281:Parathyroid Hormone; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium