Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.

In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)(2)-vitamin D (1,25(OH)(2)D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)(2)D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)(2)D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Most insights gained into the regulation of phosphate homeostasis by these factors are derived from human genetic disorders and genetically engineered mice, which are reviewed in this paper.

Vitamin D and the digestive system.

Target tissues of in vivo receptor binding and deposition of 1,25(OH)2 vitamin D3 and its oxygen analog OCT are reviewed in rats, mice, hamsters and zebra finch, identified with high-resolution microscopic autoradiography. Throughout the digestive system numerous sites with nuclear receptor binding of 3H-1,25(OH)2 vitamin D3 and 3H-OCT exist: in the oral region, epithelial cells of the oral cavity, tongue and gingiva, teeth odontoblast and ameloblast precursor pulp and stratum intermedium cells; in the parotid, submandibular and sublingual salivary glands, epithelial cells of striated ducts and granular convoluted tubules, intercalated ducts and acinar cells, as well as myoepithelial cells; in the stomach, neck mucous cells of gastric glands, endocrine cells of the antrum, and muscle cells of the pyloric sphincter; in the small and large intestine, absorptive and crypt epithelial cells; in the pancreas, predominantly islet B-cells. Perisinusoidal stellate (Ito) cells in the liver concentrate and retain variable amounts of radiolabeled compound in regions of their cytoplasm after administration of 3H-I,25(OH)2 vitamin D3 and 3H-25(OH) vitamin D3, probably sites of specific storage, similar to vitamin A. Submucosa in stomach and intestine also retain variable amounts of radiolabel, however unspecific with all compounds studied. In pilot studies with 3H-25(OH)2 vitamin D3 and 3H-24,25(OH)2 vitamin D3, no nuclear concentration was detectable. The reviewed data for vitamin D and its oxygen analogue OCT indicate genomic effects on multiple target tissues of the digestive system that involve cell proliferation and differentiation, endo- and exocrine secretion, digestion and absorption for maintaining optimal functions, with potentials for health prophylaxis and therapies.

1,25-Dihydroxycholecalciferol regulates salivary phosphate secretion in cattle.

The influence of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on salivary inorganic phosphorus (Pi) concentration and secretion was studied in two groups of four heifers, the right parotid ducts of which were chronically fitted with a re-entrant cannula. In four heifers i.v. Pi loading (5 mmol/min for 2 h) induced hyperphosphataemia associated with a decrease in plasma 1,25-(OH)2D concentration and an increase in salivary Pi concentration and secretion. In four other heifers, daily 1 alpha-hydroxycholecalciferol injections (1 microgram/kg body wt per day for 3 days) induced hyperphosphataemia associated with an increase in plasma 1,25-(OH)2D concentration and a decrease in salivary Pi concentration and secretion. These treatments had no significant effect on salivary calcium concentration and secretion. Our results indicate that plasma 1,25-(OH)2D concentrations rather than phosphataemia regulate salivary Pi concentration and secretion in cattle.

The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms.

Neural and systemic somatotrophic effects of the ultraviolet component of sunlight through the skin-vitamin D endocrine system are considered as alternate or additional to the neuroendocrine effects of the visual component of light through the retino-diencephalic input. The extensive distribution of soltriol nuclear receptor cells, revealed by autoradiography with tritium-labeled 1,25 dihydroxycholecalciferol (vitamin D, soltriol) and related effects, indicate an involvement of vitamin D-soltriol in the actinic induction of seasonal biorhythms. This is considered to be independent of the traditionally assigned effects of vitamin D on systemic calcium regulation. Skin-soltriol mediated seasonal, and to a degree daily, genomic activation involves many target regions in the brain. These include neurons in the central nucleus of the amygdala, in the linked part of the bed nucleus of the stria terminalis, in periventricular hypothalamic neurons, dorsal raphe nucleus, reticular thalamic nucleus and autonomic, endocrine as well as sensory and motor components of the brainstem and spinal cord. Additional to the eye-regulated "suprachiasmatic clock", existence of a soltriol-vitamin D regulated neural "timing circuit(s)" is proposed. Both, activational and organizational effects of soltriol on mature and developing brain regions, respectively are likely to play a role in the regulation of neuronal functions that include the modulation and entrainment of biorhythms. Soltriol's central effects correlate with peripheral effects on elements in skin, bone, teeth, kidney, intestine, heart and blood vessels, endocrine organs, and tissues of the immune and reproductive system.

Effects of parathyroid hormone, 1,25-dihydroxyvitamin D3, and prostaglandin E2 on alkaline phosphatase activity in cultured dental pulp and gingiva cells of bovine calf.

The effects of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3, and prostaglandin E2 (PGE2) on alkaline phosphatase activity on cultured dental pulp and gingiva cells of bovine calf were compared. In pulp cells, PTH, 1,25-dihydroxyvitamin D3, and PGE2 significantly increased alkaline phosphatase activity, but no increase in the enzyme activity by these factors was observed in gingiva cells. Dibutyryl cAMP also increased alkaline phosphatase activity in both types of cell, but the increase in pulp cells was greater than that in gingiva cells. Treatment of the cultured pulp cells with PTH or PGE2 significantly increased the intracellular cAMP content. These results suggest that calciotropic factors such as PTH, 1,25-dihydroxyvitamin D3, and PGE2 may be involved in the differentiation of dental pulp cells and that some of these effects (those of PTH and PGE2) are mediated by cAMP.

Renal homeostasis of calcium.

Calcium is critical for many metabolic functions. While 99% of body calcium is found as part of the structure of bone and teeth, 1% found in plasma and body cells is crucial for such functions as blood clotting, nerve impulse conduction, and muscle contraction. The homeostasis of calcium is complex because the gastrointestinal tract, the bones, and the kidneys all affect calcium balance. This manuscript reviews the functions, homeostasis, and renal handling and regulation of calcium. The major sites of renal tubular reabsorption and the related cellular mechanisms are described.

Promotion of osseointegration of anodized titanium implants with a 1α,25-dihydroxyvitamin D3 submicron particle coating.

PURPOSE: A biochemical approach to implant surface modification may offer an alternative to physicochemical and morphologic methods for obtaining desirable bone-implant interfaces. The objective of this study was to investigate the bone tissue response to anodized titanium implant surfaces coated with a poly(D,L-lactide-co-glycolide) (PLGA) solution mixed with 1α,25-diydroxyvitamin D3 (1α,25-(OH)2D3) via an electrospray technique. MATERIALS AND METHODS: Threaded implants were manufactured and anodized under 300 V at 660 Hz for 3 minutes (control group). Half of the implants were then coated with 0.15 mL of the PLGA/1α,25-(OH)2D3 solution (5 µg/implant) via electrospray (experimental group). Surface topography was evaluated using field-emission scanning electron microscopy and optical interferometry. Forty-eight implants (12 implants per group per healing period) were surgically placed in random sites in the tibiae of 12 New Zealand white rabbits. After 4 and 12 weeks of healing, undecalcified ground sections were subjected to histologic and histomorphometric analyses. RESULTS: At week 4, the mean bone-to-implant contact ratio (BIC%) over the entire length of the implant in the experimental group was 37.08% ± 10.18%, versus 28.01% ± 8.70% in the control group. The mean BIC% value in the first four consecutive threads of the experimental group was 48.64% ± 15.92%, compared to 36.11% ±13.49% in the control group (P < .05). At week 12, the mean overall BIC% values were 39.10% ± 7.68% in the experimental group and 29.53% ± 9.49% in the control group. The mean BIC% value in the first four consecutive threads of the experimental group was 51.80% ± 16.41%, versus 37.35% ± 11.77% in the control group (P < .05). CONCLUSION: The current study demonstrated that the PLGA/1α,25-(OH)2D3 solution coating resulted in submicron-sized particles, which may stimulate bone formation adjacent to the surface of implants inserted into bone.

Distinctive anabolic roles of 1,25-dihydroxyvitamin D(3) and parathyroid hormone in teeth and mandible versus long bones.

To assess the roles of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and parathyroid hormone (PTH) in hard tissue formation in oro-facial tissues, we examined the effect of either 1,25(OH)(2)D or PTH deficiency on dentin and dental alveolar bone formation and mineralization in the mandibles, and osteoblastic bone formation in long bones of 1alpha-hydroxylase knockout (1alpha(OH)ase(-/-)) mice. Compared with wild-type mice, the mineral density was decreased in the teeth and mandibles, and unmineralized dentin (predentin and biglycan immunopositive dentin) and unmineralized bone matrix in the dental alveolar bone were increased in 1alpha(OH)ase(-/-) mice. The dental volume, reparative dentin volume, and dentin sialoprotein immunopositive areas were reduced in 1alpha(OH)ase(-/-) mice. The cortical thickness, dental alveolar bone volume, and osteoblast number were all decreased significantly in the mandibles; in contrast, the osteoblast number and surface were increased in the trabecular bone of the tibiae in 1alpha(OH)ase(-/-) mice consistent with their secondary hyperparathyroidism. The expression of PTH receptor and IGF1 was reduced slightly in mandibles, but enhanced significantly in the long bones in the 1alpha(OH)ase(-/-) mice. To control for the role of secondary hyperparathyroidism, we also examined teeth and mandibles in 6-week-old PTH(-/-) mice. In these animals, dental and bone volumes in mandibles were not altered when compared with their wild-type littermates. These results suggest that 1,25(OH)(2)D(3) plays an anabolic role in both dentin and dental alveolar bone as it does in long bones, whereas PTH acts predominantly in long bones rather than mandibular bone.

A simple method to assess osteoclast-mediated bone resorption using unfractionated bone cells.

To determine osteoclastic bone resorption we established a simple assay system in which unfractionated cells obtained from femora of 13-day-old mice were cultured on a dentine slice and the number of osteoclasts and their induced pit area on the slices were measured. When the bone cells (1 x 10(5) cells/dentine slice) were cultured in the presence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or human parathyroid hormone (hPTH) for 4 days, at which time newly-formed osteoclasts were not detected, the pit area was dose-dependently increased, being a 4.3- or 4.1-fold respective increase over the control at a 10(-8) M concentration of hormones. Chick calcitonin (cCT) inhibited the osteoclastic bone resorption induced by either of these hormones. cCT alone also suppressed the bone resorption by the cells (3 x 10(5) cells/dentine slice). These findings indicate that 1,25(OH)2D3 or hPTH may mainly activate pre-existing osteoclasts, resulting in increased bone resorption, and that cCT may suppress this osteoclastic activity. When 1,25(OH)2D3 or hPTH was added to the cells pre-cultured in factor-free medium for 6 days, at which time pre-existing osteoclasts had almost degenerated, new osteoclasts were formed, resulting in an increase in pit formation. Thus this system is a useful method which could more sensitively evaluate the effects of hormones or factors on osteoclast formation and activation than other previous systems.

Cell- and stage-specific expression of vitamin D receptor and calbindin genes in rat incisor: regulation by 1,25-dihydroxyvitamin D3.

To investigate the extent of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] action and its relationships to calbindin gene expression in mineralized tissues, we have analyzed rat incisors with different probes, including a vitamin D receptor (VDR) antibody and specific cDNAs to rat calbindin-D9K and calbindin-D28K. Developmental and hormonal controls of calbindin gene expression were investigated by Northern blot analysis of ameloblast and odontoblast mRNA. Distribution and hormone-induced changes of VDR were also studied by light microscopic immunocytochemistry. A differential tissue- and stage-specific expression of the calbindin genes was observed in microdissected portions of the continuously erupting incisor. The two calbindins were expressed in ameloblasts, whereas only calbindin-D28K was expressed in odontoblasts. Moreover, in ameloblasts, expression of calbindin-D28K preceded that of calbindin-D9K. Immunoreactivity for VDR was present in all progenitor cells and progressively decreased during the differentiation process, whereas, in differentiated tissues, a hormonal upregulation was restricted to hard tissue-forming cells, i.e., ameloblasts and odontoblasts. Furthermore, calbindin gene expression appeared to be regulated by 1,25(OH)2D3. Taken together, these data indicate that ameloblasts and odontoblasts are target cells for 1,25(OH)2D3 and provide the first insights into the hormonal control of tooth genes during development.

Osteoporosis and its relationship to oral bone loss.

Osteoporosis, an age-related condition, is classified into primary and secondary types. Primary osteoporosis encompasses the postmenopausal and senile types; secondary osteoporosis occurs "secondary" to endocrine and renal diseases. Subjects affected by osteoporosis have an overall reduced bone mass and become highly susceptible to bone fractures. Dual energy x-ray absorptiometry is the method most often used to determine the risk for osteoporotic fractures. In the past decade, a number of studies have suggested a possible correlation between systemic osteoporosis and alveolar bone loss in periodontal disease pathogenesis. It appears that a clear correlation between periodontal health and the general mineral status of the skeleton is still lacking. This review addresses the pathogenesis of osteoporosis and emphasizes the multifactorial nature of bone loss. The current concepts in alveolar bone loss resulting from osteoporosis and its implications as a risk factor in periodontal disease development are also presented.

Differential epithelial and mesenchymal regulation of tooth-specific matrix proteins expression by 1,25-dihydroxyvitamin D3 in vivo.

Enamel defects have been reported in rickets and related to disturbed expression of amelogenin in ameloblasts. The present study is devoted to amelogenin, enamelin, ameloblastin, and dentin sialophosphoprotein (DSPP) expression in both the epithelium and mesenchyme of vitamin D-deficient rat incisors. Quantitative Northern blotting analysis (relatively to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA steady-state levels) was performed on microdissected cells of rachitic (-D) and control (+D) 56 day old rats. Steady-state levels of amelogenin and enamelin mRNA were significantly reduced in the -D epithelium versus the +D epithelium ones. In contrast, ameloblastin expression was slightly increased in -D epithelium. In the same samples, DSPP mRNA levels remained unchanged in -D dental mesenchyme. Comparative electron microscopy studies between +D and -D animals showed a dramatic decrease of intraprismatic enamel (amelogenin and enamelin immunoreactive) consistent with our molecular results. In conclusion, tooth formation results from the coordinated expression of several matrix proteins that may be controlled by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3].

Comparison of the effects of 1,25 dihydroxycholecalciferol and prostaglandin E2 on orthodontic tooth movement.

This study compared the effects of local administrations of prostaglandin E2 (PGE2) and 1,25-dihydroxycholecalciferol (1,25-DHCC) on orthodontic tooth movement in rats. Thirty-seven 6-week-old male Sprague-Dawley rats, weighing 160 +/- 10 g were used. Five rats served as the baseline control group. A fixed appliance system exerting 20 g of distally directed force was applied on the maxillary incisors of 32 animals for 9 days. Eight rats served as the appliance control group; 8 received a 20-microL injection of dimethyl sulfoxide (solvent for 1,25-DHCC) on days 0, 3, and 6; 8 received 20 microL of 10(-10) mol/L 1,25-DHCC on days 0, 3, and 6; 8 received a single injection of 0.1 mL of 0.1 microg PGE2 only on day 0. There was no significant difference in tooth movement between the PGE2 and the 1,25-DHCC groups. Both PGE2 and 1,25-DHCC enhanced the amount of tooth movement significantly when compared with the control group. The numbers of Howship's lacunae and capillaries on the pressure side were significantly greater in the PGE2 group than in the 1,25-DHCC group. On the other hand, the number of osteoblasts on the external surface of the alveolar bone on the pressure side was significantly greater in the 1,25-DHCC group than in the PGE2 group. Thus, 1,25-DHCC was found to be more effective in modulating bone turnover during orthodontic tooth movement, because its effects on bone formation and bone resorption were well balanced.