Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells.
Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity, and low contents of vitamin D and calcium-sensing receptors). Control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism, but the advanced stage of hyperplasia is considered irreversible. In the present study, dialysis patients with PTG hyperplasia underwent direct injection of calcitriol or maxacalcitol (OCT) into the PTG. Ultrasonography showed that this treatment had significantly reduced PTG volume and tissue analysis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method and DNA electrophoresis indicated that cellular apoptosis had been induced. The mechanism of apoptosis was evaluated in detail in uremic rats fed a high-phosphate diet. OCT or its vehicle was directly injected into the rats' PTGs. In the PTGs treated by OCT, there was a significantly increased number of TUNEL-positive PTCs and DNA electrophoresis revealed the characteristic ladder pattern of DNA fragmentation, both findings indicative of apoptosis. There was also a significant upregulation of both vitamin D and Ca-sensing receptors in the PTCs and a clear shift of the Ca-PTH response curve to the left and downward. None of these findings was observed in the PTGs treated by vehicle. This novel treatment is successful in causing regression of PTG hyperplasia. Thus, it is expected to significantly reduce the PTH level and ameliorate the abnormal bone turnover and mineral metabolism.
Shiizaki
K
K
Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, Wakayama, Japan. shiizaki@wakayama-med.ac.jp
Negi
S
S
Hatamura
I
I
Tatsuta
K
K
Shibata
M
M
Shimada
S
S
Sakaguchi
T
T
Akizawa
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002117:Calcitriol / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D053938:DNA Fragmentation / Q000187:drug effects*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000628:therapy; D008297:Male; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D014807:Vitamin D; D014815:Vitamins / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D044169:Receptors, Calcium-Sensing; D014815:Vitamins; D014807:Vitamin D; D002117:Calcitriol; C051883:maxacalcitol