New insights into mineral and skeletal regulation by active forms of vitamin D
2006; Elsevier BV; Volume: 69; Issue: 2 Linguagem: Inglês
10.1038/sj.ki.5000091
ISSN1523-1755
AutoresGeoffrey N. Hendy, Keith A. Hruska, Suresh Mathew, David Goltzman,
Tópico(s)Bone health and osteoporosis research
ResumoRecent studies in mice using genetic approaches have shed new light on the physiological effects of 1,25-dihydroxyvitamin D (1,25(OH)2D) and the vitamin D receptor (VDR) in skeletal and mineral homeostasis, and on their interaction with calcium. These studies in mice with targeted deletion of the 25-hydroxyvitamin D-1α-hydroxylase (1α(OH)ase), and of the VDR or of double mutants, have shown the discrete effects of calcium in inhibiting parathyroid hormone secretion and in enhancing bone mineralization, but overlapping effects of calcium and 1,25(OH)2D on inhibiting parathyroid growth and on normal development of the cartilaginous growth plate. The 1,25(OH)2D/VDR system is essential, however, in enhancing intestinal calcium absorption and in optimally increasing osteoclastic activation. In addition, the 1,25(OH)2D/VDR system has important anabolic effects on bone, thus defining a dual role for this system in bone turnover. These studies are revealing functions of the vitamin D/VDR system which have relevance for new concepts of the pathophysiology of renal bone disease and, in particular, of the adynamic bone disorder, and for the development of new analogs of the active form of vitamin D, which have less calcemic activity and greater skeletal anabolic effects. Recent studies in mice using genetic approaches have shed new light on the physiological effects of 1,25-dihydroxyvitamin D (1,25(OH)2D) and the vitamin D receptor (VDR) in skeletal and mineral homeostasis, and on their interaction with calcium. These studies in mice with targeted deletion of the 25-hydroxyvitamin D-1α-hydroxylase (1α(OH)ase), and of the VDR or of double mutants, have shown the discrete effects of calcium in inhibiting parathyroid hormone secretion and in enhancing bone mineralization, but overlapping effects of calcium and 1,25(OH)2D on inhibiting parathyroid growth and on normal development of the cartilaginous growth plate. The 1,25(OH)2D/VDR system is essential, however, in enhancing intestinal calcium absorption and in optimally increasing osteoclastic activation. In addition, the 1,25(OH)2D/VDR system has important anabolic effects on bone, thus defining a dual role for this system in bone turnover. These studies are revealing functions of the vitamin D/VDR system which have relevance for new concepts of the pathophysiology of renal bone disease and, in particular, of the adynamic bone disorder, and for the development of new analogs of the active form of vitamin D, which have less calcemic activity and greater skeletal anabolic effects. Circulating concentrations of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), derive from 1α-hydroxylation of 25-hydroxyvitamin D (25(OH)D) by the renal mitochondrial enzyme, 25(OH)D-1α-hydroxylase (1α(OH)ase).1.Bouillon R. Okamura W.H. Norman A.W. Structure–function relationships in the vitamin D endocrine system.Endocr Rev. 1995; 6: 200-257Google Scholar, 2.Sutton A.I. MacDonald P.N. Vitamin D: more than a ‘bone-a-fide’ hormone.Molec Endocrinol. 2003; 17: 777-791Crossref PubMed Scopus (252) Google Scholar, 3.DeLuca H.F. Overview of general physiologic features and functions of vitamin D.Am J Clin Nutr. 2004; 80: 1689S-1696SPubMed Google Scholar 1,25(OH)2D circulates bound to the vitamin D binding protein. After being taken up by target cells and bound to intracellular binding proteins, the sterol interacts with the vitamin D receptor (VDR), a member of the nuclear receptor superfamily.4.Adams J.S. Chen H. Chun R. et al.Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism.J Steroid Biochem Mol Biol. 2004; 89–90: 461-465Crossref PubMed Scopus (54) Google Scholar In the nucleus of target cells, the ligand-activated VDR heterodimerizes with the retinoid X receptor and the dimer binds to response elements on target genes.5.Jurutka P.W. Whitfield G.K. Hsieh J.-C. et al.Molecular nature of the vitamin D receptor and its role in regulation of gene expression.Rev Endocr Metab Disord. 2001; 2: 203-216Crossref PubMed Scopus (240) Google Scholar Coregulators are recruited to link the dimer to the basal transcriptional machinery and thereby modulate gene transcription. Differential interactions with the binding proteins involved in transport or intracellular chaperoning of 1,25(OH)2D3, mobilization of discrete VDR coregulators, differential effects on VDR turnover, or distinct rates or pathways of elimination of vitamin D analogs are among the mechanisms which contribute to the specific actions of newer vitamin D analogs. In addition to the canonical pathway of action described above, a number of pathways involving rapid, nongenomic effects have been described. These include interaction of the ligand with a membrane receptor, either a novel receptor or the known VDR, thereby activating cell signaling pathways.6.Norman A.W. Mizwicki M.T. Norman D.P.G. Steroid hormone rapid actions, membrane receptors and a conformational ensemble model.Nat Rev Drug Dis. 2004; 3: 27-41Crossref PubMed Scopus (496) Google Scholar, 7.Hendy G.N. Goltzman D. Does calcitriol have actions independent from the vitamin D receptor in maintaining skeletal and mineral homeostasis?.Curr Opin Nephrol Hypertens. 2005; 14: 350-354Crossref PubMed Scopus (9) Google Scholar Both the VDR and extrarenal 1α(OH)ases have been described in a variety of tissues, beyond those related to skeletal and mineral homeostasis, implicating vitamin D action in a broad range of physiologic functions. Circulating concentrations of 1,25(OH)2D have profound effects on parathyroid function, mineral metabolism, and skeletal function, which are severely disordered in chronic kidney disease (CKD). 1,25(OH)2D synthesis is impaired in CKD in part due to suppression of the 1α(OH)ase by retained phosphate and in part because of loss of renal parenchyma. As a result, low levels of calcitriol develop in stage 3 CKD. This results in reduced calcium absorption, which, with hyperphosphatemia due to impaired renal tubular function and decreased bone formation, leads to hypocalcemia. Hypocalcemia, low 1,25(OH)2D, and phosphate retention can lead to the development of secondary hyperparathyroidism and disordered skeletal remodeling, which may be accentuated by decreased levels of VDR and diminished levels of the calcium sensing receptor in hyperplastic parathyroid tissue. The skeletal consequence of secondary hyperparathyroidism is a disorder of bone remodeling referred to as osteitis fibrosa. Secondary hyperparathyroidism also contributes to the reduced longitudinal bone growth that occurs in CKD, affecting the pediatric population due to effects of the derangements of Ca, Pi, and vitamin D on the cartilaginous growth plate. Several ‘knockout’ mouse models, with targeted disruption of either the 1α(OH)ase8.Panda D.K. Miao D. Tremblay M.L. et al.Targeted abalation of the 25-hydroxyvitamin D-1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction.Proc Natl Acad Sci USA. 2001; 98: 7498-7503Crossref PubMed Scopus (529) Google Scholar, 9.Dardenne O. Prud'homme J. Arabian A. et al.Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets.Endocrinology. 2001; 142: 3135-3141Crossref PubMed Scopus (286) Google Scholar or the VDR10.Li Y.C. Pirro A.E. Amling M. et al.Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.Proc Natl Acad Sci USA. 1997; 94: 9831-9835Crossref PubMed Scopus (809) Google Scholar, 11.Yoshizawa T. Handa Y. Uematsu Y. et al.Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.Nat Genet. 1997; 16: 391-396Crossref PubMed Scopus (974) Google Scholar, 12.Erben R.G. Soegiarto D.W. Weber K. et al.Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D.Molec Endocrinol. 2002; 16: 1524-1537Crossref PubMed Scopus (248) Google Scholar gene have been generated (1α(OH)ase-/- and VDR-/- mice, respectively). These represent murine models of the inherited human disorders, vitamin D-dependent rickets type I and type II, respectively.13.Fraser D. Kooh S.W. Kind H.P. et al.Pathogenesis of hereditary vitamin D-dependent rickets: an inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1α,25-dihroxyvitamin D.N Engl J Med. 1973; 289: 817-822Crossref PubMed Scopus (325) Google Scholar, 14.Beer S. Tieder M. Kohelet D. et al.Vitamin D resistant rickets with alopecia: a form of end organ resistance to 1,25-dihydroxyvitaminD.Clin Endocrinol. 1981; 14: 395-402Crossref PubMed Scopus (57) Google Scholar We have used these models and double null mutants (1α(OH)ase-/-VDR-/-) to examine the effects of the 1,25(OH)2D/VDR system on mineral, parathyroid, and skeletal homeostasis.15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar The study of the mechanisms underlying the 1,25(OH)2D- and VDR-deficient phenotypes in these mouse mutants has been facilitated by the correction of the hypocalcemia, which these animals exhibit, by a ‘rescue’ diet containing high concentrations of calcium, phosphorus, and lactose.16.Li Y.C. Amling M. Pirro A.E. et al.Normalization by dietary means prevents hyperparathyroidism, rickets and osteomalacia, but not alopecia in vitamin D receptor-ablated mice.Endocrinology. 1998; 139: 4391-4396Crossref PubMed Scopus (395) Google Scholar, 17.Amling M. Priemel M. Holtzman T. et al.Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses.Endocrinology. 1999; 140: 4982-4987Crossref PubMed Scopus (374) Google Scholar, 18.Dardenne O. Prud'homme J. Hacking S.A. et al.Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1).Bone. 2001; 32: 332-340Abstract Full Text Full Text PDF Scopus (128) Google Scholar These genetic models and the environmental manipulations of the models have therefore provided powerful probes to dissect in vivo the discrete and overlapping contributions of vitamin D, calcium, and parathyroid hormone (PTH) to the endocrine control of skeletal and mineral metabolism.19.Goltzman D. Miao D. Panda D.K. Hendy G.N. Effects of calcium and of the vitamin D system on skeletal and calcium homeostasis: lessons from genetic models.J Steroid Biochem Molec Biol. 2004; 89–90: 485-489Crossref PubMed Scopus (66) Google Scholar Optimal dietary calcium absorption in the 1α(OH)ase-/- and the VDR-/- mice required an intact 1,25(OH)2D/VDR system. In more recent studies in young 1α(OH)ase-/- mice and mice with targeted ablation of the PTH gene (PTH-/-), we found that both 1,25(OH)2D and PTH could independently and co-operatively modulate renal calcium transporters including the luminal epithelial channel transient receptor potential-vanilloid-5 (TRPV5), the intracellular calcium-binding proteins calbindin-D28K and calbindin-D9K, and the basolateral membrane sodium–calcium exchanger, NCX1.20.Xue Y. Karaplis A.C. Hendy G.N. et al.Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development.Hum Molec Genet. 2005; 14: 1515-1528Crossref PubMed Scopus (86) Google Scholar These results are consistent with the actions of 1,25(OH)2D reported in other 1α(OH)ase-/- models.21.Hoenderop J.G. Dardenne O. Van Abel M. et al.Modulation of renal Ca2+ transport protein genes by dietary Ca2+ and 1,25-dihydroxyvitamin D3 in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice.FASEB J. 2002; 16: 1398-1406Crossref PubMed Scopus (215) Google Scholar In the 1α(OH)ase-/- and VDR-/- models, secretion of intact PTH was modulated primarily by ambient serum calcium in that normalization of serum calcium with the rescue diet normalized circulating PTH even in the absence of 1,25(OH)2D or the VDR. Nevertheless, the parathyroid gland hyperplasia, which the mutants exhibited, persisted when calcium alone was normalized. The combination of normal extracellular calcium and 1,25(OH)2D (apparently independently of the VDR) was required for normalization of parathyroid gland size. The results indicate that calcium cannot entirely substitute for deficient vitamin D in maintaining parathyroid homeostasis, and that the two agents act co-operatively in modulating parathyroid cell proliferation. On a normal- or high-calcium lactose-free intake, all three hypocalcemic mutant mouse models, the 1α(OH)ase-/-, VDR-/-, and 1α(OH)ase-/-VDR-/- mice, develop characteristic skeletal rachitic changes of enlarged and distorted cartilaginous long bones with widened hypertrophic zones.8.Panda D.K. Miao D. Tremblay M.L. et al.Targeted abalation of the 25-hydroxyvitamin D-1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction.Proc Natl Acad Sci USA. 2001; 98: 7498-7503Crossref PubMed Scopus (529) Google Scholar, 9.Dardenne O. Prud'homme J. Arabian A. et al.Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets.Endocrinology. 2001; 142: 3135-3141Crossref PubMed Scopus (286) Google Scholar, 10.Li Y.C. Pirro A.E. Amling M. et al.Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.Proc Natl Acad Sci USA. 1997; 94: 9831-9835Crossref PubMed Scopus (809) Google Scholar, 11.Yoshizawa T. Handa Y. Uematsu Y. et al.Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.Nat Genet. 1997; 16: 391-396Crossref PubMed Scopus (974) Google Scholar, 15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar, 18.Dardenne O. Prud'homme J. Hacking S.A. et al.Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1).Bone. 2001; 32: 332-340Abstract Full Text Full Text PDF Scopus (128) Google Scholar These abnormalities appear less severe in VDR-/- mice with elevated endogenous 1,25(OH)2D levels than in the other two mutants, suggesting that 1,25(OH)2D may modulate cartilage function independently of the VDR. Nevertheless, 1,25(OH)2D per se cannot normalize the growth plate if hypocalcemia is not normalized and, conversely, elimination of hypocalcemia with the rescue diet does not completely normalize the growth plate in the mouse models that have deficient endogenous 1,25(OH)2D. Consequently, both calcium and 1,25(OH)2D together appear necessary for normal development of the cartilaginous growth plate, analogous to the effect on parathyroid growth. Previous studies in double-null mutants of the VDR and of the retinoid X receptor γ have suggested the existence of a novel VDR in the cartilaginous growth plate with which 1,25(OH)2D may interact.22.Yagishita N. Yamamoto Y. Yoshizawa T. et al.Aberrant growth plate development in VDR/RXRγ double null mutant mice.Endocrinology. 2001; 142: 5332-5341Crossref PubMed Scopus (40) Google Scholar In addition, rapid, nongenomic effects have been reported in cartilage cells.6.Norman A.W. Mizwicki M.T. Norman D.P.G. Steroid hormone rapid actions, membrane receptors and a conformational ensemble model.Nat Rev Drug Dis. 2004; 3: 27-41Crossref PubMed Scopus (496) Google Scholar, 7.Hendy G.N. Goltzman D. Does calcitriol have actions independent from the vitamin D receptor in maintaining skeletal and mineral homeostasis?.Curr Opin Nephrol Hypertens. 2005; 14: 350-354Crossref PubMed Scopus (9) Google Scholar Our findings are consistent with one or other or both of these possibilities. Mineralization of both cartilage and bone is severely impaired in all mutants (the 1α(OH)ase-/-, VDR-/-, and 1α(OH)ase-/-, VDR-/- models) that are hypocalcemic on either a lactose-free-normal or high-calcium intake.15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar However, cartilage mineralization and bone mineralization are normalized in all models when hypocalcemia is eliminated by the rescue diet. Administration of exogenous 1,25(OH)2D3 normalizes mineralization only when serum calcium is normalized, that is, in the 1α(OH)ase-/- model.15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar Consequently, the major determinant of skeletal mineralization appears to be the ambient concentration of extracellular calcium (and phosphate) and the 1,25(OH)2D/VDR system appears to play no direct role in this process. Osteoblast numbers, bone formation, and bone volume are markedly increased in all hypocalcemic animals (1α(OH)ase-/-, VDR-/-, and 1α(OH)ase-/- VDR-/- mice) on either a lactose-free, normal-calcium intake,8.Panda D.K. Miao D. Tremblay M.L. et al.Targeted abalation of the 25-hydroxyvitamin D-1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction.Proc Natl Acad Sci USA. 2001; 98: 7498-7503Crossref PubMed Scopus (529) Google Scholar, 9.Dardenne O. Prud'homme J. Arabian A. et al.Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets.Endocrinology. 2001; 142: 3135-3141Crossref PubMed Scopus (286) Google Scholar, 10.Li Y.C. Pirro A.E. Amling M. et al.Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.Proc Natl Acad Sci USA. 1997; 94: 9831-9835Crossref PubMed Scopus (809) Google Scholar or a lactose-free, high-calcium intake.15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar This appears to be due to the anabolic effect of PTH, which is markedly elevated in association with the severe secondary hyperparathyroidism in these animals. Increased serum alkaline phosphatase reflects the increased osteoblastic stimulation by PTH and is normalized when PTH is normalized by eliminating the secondary hyperparathyroidism. The increased bone volume is largely due to increased unmineralized bone matrix however, as a result of the ambient hypocalcemia. Interestingly, a sustained elevation of increased PTH is generally associated with increased osteoclastic bone resorption as well as increased bone formation. Nevertheless, osteoclast number and resorbing surface are not appreciably elevated in these models compared to wild-type, suggesting an inappropriate response to the increased PTH. Furthermore, in our studies,15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar a decrease in the average osteoclast size was seen in the 1,25(OH)2D- and/or VDR-deficient mutant animals with secondary hyperparathyroidism. This suggests that there is uncoupling of bone turnover in the presence of a defective 1,25(OH)2D/VDR system and the relatively low resorption may contribute, with increased osteoblast activity, to the increased bone volume. Indeed, previous studies with osteoclast-generating models in vitro have shown that osteoblastic cells from VDR-/- mice in culture with normal spleen cells could not sustain 1,25(OH)2D-stimulated osteoclast production, although PTH could.23.Takeda S. Yoshizawa T. Nagai Y. et al.Stimulation of osteoclast formation by 1,25-dihydroxyvitamin D requires its binding to vitamin D receptor (VDR) in osteoblastic cells: studies using VDR knockout mice.Endocrinology. 1999; 140: 1005-1008Crossref PubMed Scopus (123) Google Scholar Therefore, although PTH and local modulators of bone resorption may sustain a normal level of osteoclastic resorption in these models, an intact 1,25(OH)2D/VDR system is required for an optimal osteoclastic response to increased PTH. In view of the fact that osteoclast/chondroclast production at the chondro-osseous junction may also be defective, diminished removal of hypertrophic chondrocytes may occur in this region, leading to altered cartilage growth plate remodeling. Therefore, the enlargement of the cartilaginous growth plate, and notably the hypertrophic zone, may also be in part due to reduced activity of the 1,25(OH)2D/VDR system on the chondroclast/osteoclast system.17.Amling M. Priemel M. Holtzman T. et al.Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses.Endocrinology. 1999; 140: 4982-4987Crossref PubMed Scopus (374) Google Scholar In our studies we also found that in all three mutant models, that is, in the absence of 1,25(OH)2D, VDR, or both 1,25(OH)2D and VDR, when serum calcium was normalized by the rescue diet and secondary hyperparathyroidism was prevented, osteoblast numbers, mineral apposition rate, and bone volume were suppressed below the levels seen in wild-type mice.15.Panda D.K. Miao D. Boliver I. et al.Inactivation of the 25-hydroxyvitamin D-1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis.J Biol Chem. 2004; 279: 16754-16766Crossref PubMed Scopus (342) Google Scholar This showed that, when the 1,25(OH)2D/VDR system is deficient in the presence of normal PTH and normal calcium, a requirement of the 1,25(OH)2D/VDR system for baseline bone anabolism can be unmasked. The 1,25(OH)2D/VDR system therefore appears to exert an anabolic effect, which is necessary to sustain basal bone-forming activity. This inhibition of bone formation was not previously observed in either VDR-/- or 1α(OH)ase-/- mice on the rescue diet and may reflect the older age of our mice at the time of analysis. Furthermore, other studies have also pointed to an anabolic effect of 1,25(OH)2D,24.van Leeuwen J.P. van Driel M. van den Bemd G.J. Pols H.A. Vitamin D control of osteoblast function and bone extracellular matrix mineralization.Crit Rev Eukaryot Gene Expr. 2001; 11: 199-226PubMed Google Scholar, 25.van Driel M. Pols H.A. van Leeuwen J.P. Osteoblast differentiation and control by vitamin D and vitamin D metabolites.Curr Pharm Des. 2004; 10: 2535-2555Crossref PubMed Scopus (125) Google Scholar, 26.Reszka A.A. Pun S. Freedman L.P. Kimmel D.B. The anabolic effects of 1,25(OH)2vitamin D3 revealed by combining with alendronate.Endocrine Society Meeting. 2005Google Scholar supporting the observations in our model. Our studies therefore suggest that 1,25(OH)2D may exert effects on both bone resorption and bone formation analogous to those of PTH. To better understand the relative contributions of 1,25(OH)2D and PTH to bone anabolism, we recently compared 1α(OH)ase-/- mice to PTH-/- mice.20.Xue Y. Karaplis A.C. Hendy G.N. et al.Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development.Hum Molec Genet. 2005; 14: 1515-1528Crossref PubMed Scopus (86) Google Scholar Reduced osteoblastic bone formation in the metaphyseal region was seen in both mutants, confirming our findings of a requirement for endogenous 1,25(OH)2D as well as for endogenous PTH for bone anabolism. PTH deficiency however caused only a slight reduction in long bone length but a more marked reduction in trabecular bone volume in these models, whereas 1α(OH)ase ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length. Therefore, although both 1,25(OH)2D and PTH can affect long bone growth and trabecular bone growth, PTH plays a predominant role in appositional bone growth, whereas 1,25(OH)2D acts predominantly on endochondral bone formation. We subsequently confirmed these findings by administering exogenous 1,25(OH)2D3 (calcitriol) and PTH to these animals.27.Xue Y. Goltzman D. Karaplis A.C. et al.PTH and 1,25-dihydroxyvitamin D3 each independently exert skeletal anabolic effects and improve mineral ion homeostasis in mice which are homozygous for both the 1α-hydroxylase and PTH null alleles.J Bone Miner Res. 2005; 20: S51Google Scholar Consequently, both 1,25(OH)2D and PTH exert anabolic effects that are discrete but complementary. Overall therefore, these genetic models have provided important new insights into the role of the active form of vitamin D in mineral and skeletal homeostasis (Table 1). The actions on parathyroid growth, on regulating the development of the epiphyseal growth plate, and on regulating bone formation seem of particular relevance for the mineral and skeletal alterations which occur in both pediatric and adult kidney disease, and improved knowledge of the physiology of the vitamin D system may lead to improved design and use of vitamin D analogs in CKD.Table 1Effects of 1,25(OH)2D, calcium, and PTH on selected parameters of mineral and skeletal metabolism based on in vivo studies in genetic modelsEffectorsa+, stimulatory effect; -inhibitory effect; no symbol indicates no effect or effect not examined.Parameters1,25(OH)2 D/VDRCa1,25(OH)2 D+CaPTHCalcium absorption+Renal calcium transporters++Parathyroid secretion-Parathyroid growth-Cartilaginous growth plate development+Endochondral bone formation++Bone mineralization+Appositional bone formation+++Bone volume+Bone resorption – osteoclastic activity++Bone formation – osteoblastic activity++1α-(OH)ase activity--+24-(OH)ase activity++-a +, stimulatory effect; -inhibitory effect; no symbol indicates no effect or effect not examined. Open table in a new tab In patients with CKD, placebo-controlled trials have demonstrated that administration of daily oral calcitriol reduced PTH levels and improved bone biopsy findings.28.Nordal K.P. Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure.J Clin Endocrinol Metab. 1988; 67: 929-936Crossref PubMed Scopus (114) Google Scholar, 29.Coen G. Mazzaferro S. Bonucci E. et al.Treatment of secondary hyperparathyroidism of pre dialysis chronic renal failure with low doses of 1,25(OH)2D3: humoral and histomorphometric results.Miner Electrolyte Metab. 1986; 12: 375-382PubMed Google Scholar Concerns regarding the safety of such therapy related to deterioration of kidney function were addressed, demonstrating that the rate of decline in glomerular filtration rate did not differ between placebo- and vitamin D-treated patients.28.Nordal K.P. Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure.J Clin Endocrinol Metab. 1988; 67: 929-936Crossref PubMed Scopus (114) Google Scholar, 30.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar Nevertheless, despite oral daily regimens of calcitriol or alfacalcidol, secondary hyperparathyroidism remained the predominant bone lesion observed, especially in dialysis patients and the younger age groups.31.Mathias R. Salusky I. Harman W. et al.Renal bone disease in pediatric and young adult patients on hemodialysis in a children's hospital.J Am Soc Nephrol. 1993; 3: 1938-1946PubMed Google Scholar, 32.Goodman W.G. Salusky I.B. Evolution of secondary hyperparathyroidism during daily oral calcitriol therapy in pediatric renal osteodystrophy.Contrib Nephrol. 1991; 90: 189-195Crossref PubMed Google Scholar, 33.Hamdy N.A. Kanis J.A. Beneton N.N.C. et al.Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.Br Med J. 1995; 310: 358-363Crossref PubMed Scopus (302) Google Scholar The introduction of intravenous calcitriol was associated with marked reductions in PTH levels and bone turnover in hemodialysis patients.34.Slatopolsky E. Weerts C. Thielan J. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients.J Clin Invest. 1984; 74: 2136-2143Crossref PubMed Scopus (641) Google Scholar Oral intermittent regimens were subsequently shown to be as effective despite the greater bioavailability of intravenous calcitriol.35.Salusky I.B. Goodman W.G. Norris K.C. et al.Bioavailability of calcitriol after oral, intrave
Referência(s)