Diminished Internalization and Action of 1,25- Dihydroxyvitamin D₃in Dermal Fibroblasts Cultured from New World Primates*

Abstract

We investigated the occurrence of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-resistant osteomalacia in the New World primate colony of Saguinus imperator at the Los Angeles Zoo. The mean serum concentration of 1,25-(OH)2D3 was elevated 5-fold in the New World primates compared to that in their Old World counterparts. The specific internalization of 0.6 nM [3H]1,25-(OH)2D3 by cultured dermal fibroblasts from New World primates was reduced 75% compared to that by cells from Old World primates or man. The decrease in hormone uptake resulted from a decrease in the number of high affinity intracellular binding sites for 1,25-(OH)2D3 and apparently caused a 90-95% reduction in 1,25-(OH)2D3-induced 25-hydroxyvitamin-D3-24-hydroxylase activity. There was no alteration in the capacity or avidity of New World primate serum for 1,25-(OH)2D3 compared to that of serum from Old World primates. These data suggest that the occurrence of vitamin D-resistant osteomalacia in New World primates is the result of decreased high affinity, receptor-mediated uptake of 1,25-(OH)2D3 by the target cell.

Endogenous blockade of 1,25-dihydroxyvitamin D-receptor binding in New World primate cells.

“…This possibility is unlikely in that one would expect such a change in the VDR to result in a concomitant change in the affinity of the VDR for 1,25(OH)2-D3. Previous reports from us (2,8) (8). Furthermore, diminished VDR-hormone binding activity persists in nuclear extracts of platyrrhine cells (Fig.…”

“…The vitamin D endocrine system in many genera of New World primates (platyrrhini) is characterized by a compen-sated form of target organ resistance to the active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2-D3) (1)(2)(3)(4)(5). When compared with Old World primates (catarrhini), the platyrrhine phenotype is typified by: (a) high circulating concentrations of 1 ,25(OH)2-D in the absence ofhyperparathyroidism (6); (b) the development of vitamin D-deficient rickets and osteomalacia in some captive platyrrhine species when environmental sunlight exposure is limited (2,5); (c) a decrease in the cellular content of high affinity receptor for 1,25(OH)2-D3 (VDR)' demonstrable by radiolabeled ligand binding analyses (2,4,7,8); and (d) a decrease in cellular indices of 1,25(OH)2-D3-VDR-directed bioaction without an apparent alteration in the nuclear localization and binding of the VDR-hormone complex (2).…”

“…When compared with Old World primates (catarrhini), the platyrrhine phenotype is typified by: (a) high circulating concentrations of 1 ,25(OH)2-D in the absence ofhyperparathyroidism (6); (b) the development of vitamin D-deficient rickets and osteomalacia in some captive platyrrhine species when environmental sunlight exposure is limited (2,5); (c) a decrease in the cellular content of high affinity receptor for 1,25(OH)2-D3 (VDR)' demonstrable by radiolabeled ligand binding analyses (2,4,7,8); and (d) a decrease in cellular indices of 1,25(OH)2-D3-VDR-directed bioaction without an apparent alteration in the nuclear localization and binding of the VDR-hormone complex (2). Similar observations have been made in platyrrhini for other steroid hormones including glucocorticoids, sex steroids, and mineralocorticoids (9).…”

An Hsp27-related, Dominant-negative-acting Intracellular Estradiol-binding Protein

“…In recent studies, using steroid hormone-resistant NWP cells as a model, we have characterized two further mechanisms involved in the modulation of steroid hormone receptor action; these NWP cells demonstrate tissue resistance to vitamin D and estrogen in the face of normal expression of receptors for 1,25(OH) 2 D 3 and E 2 , respectively (8,10). Hormone resistance is caused by overexpression of two distinct classes of epigenetic factors.…”

“…A central point of distinction between NWPs and OWPs resides in the fact that NWPs display relative resistance to adrenal, gonadal, and vitamin D sterol/steroid hormones (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The precise mechanism for this remains unclear but does not involve aberrant expression of nuclear receptors for specific steroid hormones (12,13), the principal cause of hormone resistance in humans (14).…”