Receptors for 1α,25(OH)2D3: Past, present, and future

Abstract

So what does the future hold with respect to the steroid receptor timeline? One suggestion is embodied in the paradigm of cell E (Fig. 1). In cell E, a third vitamin D-related receptor has been added to the paradigm; this is a putative receptor for 24R,25(OH)2D3. Briefly, what are some of the arguments pro and con on this topic? Some readers undoubtedly believe that 24R,25(OH)2D3 is only a manifestation of the activity of the 25(OH)D3-24-hydroxylase (24-hydroxylase) acting to inactivate 1α,25(OH)2D3, as has been suggested by De Luca and Suda. The alternative view as originally promulgated by Henry and Norman is that both 24R,25- dihydroxyvitamin and 1α,25(OH)2D3 are indispensable for normal calcium and phosphorus homeostasis. More recent biological results indicate that there is a 3-fold induction of the renal 24-hydroxylase and increased serum 24R,25(OH)2D3 levels, which are correlated with the healing process after imposition of a chick tibial fracture. Another study suggests an important role for 24R,25(OH)2D3 (but not 24S,25(OH)2D3) in the fracture-healing process of a tibia which has experienced a fracture. Thus, if 24R,25(OH)2D3 does have unique biological actions separate and distinct from 1α,25(OH)2D3, then it seems reasonable to postulate the existence of a receptor for 24R,25(OH)2D3. Until recently there has been little convincing data on that point. However, there is one preliminary communication that provides evidence for the existence of a receptor with stereospecificity for 24R,25(OH)2D3, which is present in the membrane fraction of the fracture- healing callus of the tibia of young chicks. Another form of support for the biological importance of 24R,25(OH)2D3 comes from the elegant study of St. Arnaud who engineered a knock-out of the 24-hydroxylase gene. Intriguingly, the homozygous mice displayed a phenotype that could reflect essential biological functions of 24R,25(OH)2D3. About half of the mutant homozygote mice born from heterozygote females died before weaning. Bone development of those survivors was abnormal in homozygous mutants born of homozygous females. Histological analyses of the bones from these mice revealed an accumulation of unmineralized matrix at sites of intramembranous ossification, particularly the calvaria and exocortical surface of long bones. If there is, indeed, a specific receptor for 24R,25(OH)2D3, then readers should beware of still another terminology problem describing the receptors operative in the vitamin D endocrine system. Can we live with a VDR(nuc-1,25D), VDR(mem-1,25D), and VDR(mem-24,25-D)? With the possible existence of three vitamin D-related receptors, and one with a second vitamin D metabolite ligand, at the very least it will be essential for authors when writing, and speakers at meetings to discontinue their use of the generic term 'vitamin D receptor' and the acronym VDR. Of course, it will remain to the future, probably into the next millennium, to learn whether paradigm cells C, D, or E or some other model are reasonable descriptions of the biological reality of vitamin D-derived seco-steroid metabolite receptors that mediate the myriad responses associated with the vitamin D endocrine system. One of the reasons to introduce the steroid receptor timeline with its five paradigm models of 1α,25(OH)2D3 receptors (Fig. 1) into this editorial concerning the accompanying paper in this issue of JBMR, is to emphasize to the reader that the seemingly simple concept of steroid receptor action has, in fact, undergone a remarkable evolution over the past 35 years. Concepts and models that were firmly in place in the 1975 cell B paradigm are now gone and replaced by new models. Thus, the concept of a chondrocyte membrane receptor for 1α,25(OH)2D3 advanced by the laboratories of Boyan and Nemere is, to this author's eye, another reasonable and logical data point on the steroid receptor timeline. I encourage interested readers to stay tuned. It seems unlikely that there will be no further surprises in the vitamin D endocrine system!.