ABSTRACT

Mineral, hormonal and skeletal changes were determined in vitamin D-deficient (−D) and vitamin Dreplete (+D) mother rats and in their litters on day 20 of lactation. These results were compared with those obtained in −D mothers and pups, after giving the mothers an oral supplement (10 i.u. vitamin D₃/day) during the period of lactation (20 days). Compared to +D animals, both −D lactating mothers and their pups exhibited extremely low plasma levels of 25-hydroxyvitamin D₃ (25-OH-D₃), diminished 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) and increased levels of immunoreactive parathyroid hormone (iPTH). Vitamin D-deficient mothers also had higher levels of calcitonin and lower levels of prolactin than +D mothers. All − D animals (mothers and pups) showed increased osteoclastic bone resorption and severe osteomalacia as shown by decreased bone ash, decreased calcification rate and increased endosteal osteoid surface, volume and thickness. In mothers treated with vitamin D₃ during lactation, nearly all the plasma variables measured, as well as bone histomorphometric features, were normal. In contrast, their pups still showed rickets and osteomalacia, despite normal levels of 25-OH-D₃ and calcium in the plasma. These pups had raised plasma levels of 1,25(OH)₂D₃ and iPTH associated with persistent stimulation of bone resorption. This study showed that (1) severe vitamin D deficiency in lactating rats produced marked osteomalacia and secondary hyperparathyroidism in both mothers and pups, and (2) vitamin D treatment of − D mother rats during lactation (10 i.u. vitamin D₃/day) reversed the mineral, hormonal and skeletal abnormalities in mothers but not in pups.

J. Endocr. (1985) 105, 303–309

Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancreatic islet. Recent data in transgenic mice suggest that PTHrP might modulate islet mass and insulin secretion. In the present study, we assessed the effect of the N-terminal PTH-like region of PTHrP on DNA synthesis in isolated rat islets. PTHrP (1-34), between 1 pM and 10 nM, for 48 h stimulated []thymidine incorporation into rat islets. This effect was maximally induced, about 2.5-fold over control, by 10 pM of this peptide, decreasing thereafter. In contrast, PTHrP (38-64) amide or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using reverse transcription followed by PCR, we confirmed that rat islets express PTHrP and the type I PTH/PTHrP receptor. Addition of a neutralizing anti-PTHrP antibody to the incubation medium of proliferating islets decreased islet DNA synthesis by 30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, but not by 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-myristate-13-acetate for 48 h also increased DNA synthesis 2-fold over controls in islets. PTHrP (1-34), at 100 nM, in contrast to 50 microM forskolin or 10 mM NaF, failed to affect adenylate cyclase activity in islet membranes. PTHrP, at 30 pM, was also found to increase 2-fold insulin released into the islet-conditioned medium within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet growth and/or function by a PKC-mediated mechanism.