1. ¹Centre de Recherche, Centre hospitalier de l'Université de Montréal (CHUM)—Hôpital Saint-Luc, Montréal, Quebec, Canada
2. ²Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
3. ³Immutopics International, San Clemente, California, USA
4. ⁴NPS Pharmaceuticals, Toronto, Ontario, Canada

Correspondence: P D'Amour, Centre de recherché, Centre hospitalier de l'Université de Montréal (CHUM)—Hôpital Saint-Luc, 264, boul. René-Lévesque est, Montréal, Quebec, Canada H2X 1P1. E-mail: rechcalcium.chum@ssss.gouv.qc.ca

Received 20 March 2007; Revised 19 June 2007; Accepted 10 July 2007; Published online 5 September 2007.

Abstract

Carboxyl (C)-terminal fragments of parathyroid hormone (PTH) oppose the calcemic, phosphaturic, and bone-resorbing effects of active hormone. To study the action of these fragments on 1,25(OH)₂D (1,25-dihydroxyvitamin D) synthesis, we infused parathyroidectomized rats with human or rat active 1–34 or 1–84 PTH at doses selected to produce similar calcemic responses. Human active PTH influenced neither phosphate nor 1,25(OH)₂D concentrations. However, active 1–34 rat PTH decreased phosphate to the same level as vehicle-treated rats and increased 1,25(OH)₂D to very high levels, whereas active 1–84 PTH decreased phosphate but maintained 1,25(OH)₂D. As the latter effect could have been due to C-terminal fragment generation during its metabolic breakdown, we infused a mixture of rat C-terminal fragments alone or with rat 1–34. The C-terminal fragments decreased 1,25(OH)₂D and prevented hypocalcemic-induced 1,25(OH)₂D synthesis. When infused with active rat 1–34, they lowered the 1,25(OH)₂D level to that seen with intact rat 1–84. The C-terminal fragments did not influence either basal or rat 1–34- or 1–84-induced CYP27B1 mRNA levels, suggesting that their inhibitory effects on 1,25(OH)₂D synthesis appears to be post-transcriptional.