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Fellow Seminar • Topic: Vitamin D: a pleiotropic hormone Comment :洪振傑 醫師 報告人員:F2 張春偉 報告時間:99-09-15 OUTLINE • VITAMIN D – NORMAL METABOLISM • VITAMIN D IN BONE & CALCIUM HOMEOSTASIS • VITAMIN D & CANCER • VITAMIN D AS IMMUNE MODULATOR • CARDIOVASCULAR & METABOLIC ACTIONS • RENAL PROTECTION • CLINICAL PERSPECTIVES VITAMIN D - NORMAL METABOLISM • In kidney, mitochondria of epithelial cells in the proximal nephron reabsorption of 25-hydroxyvitamin D + DBP from tubular fluid – By megalin-dependent mechanism • Calcitriol is then released into peritubular blood – Circulates in plasma again bound to DBP Vitamin D binding protein • • • • • DBP ~ 58-kDa protein synthesized in the liver Human serum levels: 4 - 8 μM Half life: 3 days The parent vitamin D, 25(OH)D, & 1,25(OH)2D are carried in the circulation by DBP – But the greatest affinity is for 25(OH)D Vitamin D binding protein • Primary role – Maintain stable serum stores of vitamin D metabolites & modulate the rates of bioavailability, activation, & end organ responsiveness • Deficiency of DBP – Occur in nephrotic syndrome due to urinary protein losses – Leading to low 25(OH)D serum levels Genomic mechanism • At the cellular level, receptor (megalin)– mediated endocytosis of both calcidiol & calcitriol • Inside the cell, 1,25(OH)2D – Inactivated by mitochondrial 24-hydroxylase – Or bind to the VDR in the cytoplasm • VDR-ligand binding occurred => VDR translocates to the nucleus • => Heterodimerizes with the retinoid X receptor Genomic mechanism • This complex binds the vitamin D response element of target genes • Recruits transcription factors & corepressors/activators that modulate the transcription • These corepressors & coactivators appear to be specific for the ligand – Different forms & analogs of vitamin D may produce different effects Nongenomic • Exert biologic effects over periods of time that are too short to be explained by genomic mechanisms • A discrete receptor, or membraneassociated protein – Distinct from the VDR may mediate these rapid nongenomic actions Transcaltachia • Increases in intestinal Ca transport within 10 - 15 minutes after adding 1,25dihydroxyvitamin D to fluid used to perfuse the lumen of the proximal small intestine Impact of Chronic Kidney Disease on Vitamin D Metabolism • Cross-sectional studies – 1,25-dihydroxyvitamin D decrease progressively as renal function declines – Reductions in renal synthesis • Adversely affects intestinal Ca absorption => modest reductions in serum Ca concentration • => Hypocalciuria • Several mechanisms involved Consequences of Impaired Renal Calcitriol Synthesis in Chronic Kidney Disease • Calcitriol modulates the expression of several key proteins responsible for the transepithelial movement of Ca – Not only in intestine but also in kidney • Calbindins – Vitamin D-dependent proteins – Buffer free Ca within the cytoplasm of epithelial cells in Ca-transporting epithelia – Translocation of Ca from the apical to the basolateral cell membrane • Calcitriol + Ca modulates the expression of 2 proteins • Vanilloid family of transient receptor potential (TRP) proteins • TRPV-5 & TRPV-6 • Constitutively activated Ca channel • Mediates Ca uptake across the apical membrane of renal & intestinal epithelial cells Extrarenal Calcitriol Synthesis • Other tissues also express the 25hydroxyvitamin D-1-α-hydroxylase • => 1,25-dihydroxyvitamin D synthesis regulated in a tissue-specific manner • => serve as autocrine or paracrine VITAMIN D IN BONE & CALCIUM HOMEOSTASIS • 1,25(OH)2D3 – Major calcitropic hormone – Keep the plasma Ca2+ within narrow limits – Renal production regulated by 2 hormones • PTH – Hypocalcemia => secretion of PTH by the parathyroid gland – PTH targets the kidney • Decrease Ca2+ excretion, inhibit phosphate reabsorption, & stimulate 1,25(OH)2D3 production FGF23 • 1,25(OH)2D3 stimulates the secretion of FGF23 by the osteocytes • Major phosphaturic hormone • Inhibiting renal phosphate reabsorption • By the specific transporter NaPiT2a • Decrease renal production of 1,25(OH)2D3 • Genetic deficiencies in 1,25(OH)2D3 – Loss of CYP27B1 or VDR – => hypocalcemia, hyperparathyroidism, hypophoshatemia, rickets, & osteomalacia • The phenotype can largely be corrected by administration of a high Ca diet – Bypasses 1,25(OH)2D3 -mediated, Ca2+ absorption - Endocr Rev 2008;29: 726–776 • Reintroducing VDR in the intestine of VDR null mice rescued the hypocalcemia & the bone phenotype - Gastroenterology 2009; 136:1317–1327 - J Bone Miner Res 2008; 23: S104 • The proteins involved in this active intestinal Ca2+ transport remain poorly defined. • TRPV6, Calbindin – Main mediators of 1,25(OH)2D3 -induced intestinal Ca2+ absorption • Inactivation of TRPV6 & calbindin D9k not impair intestinal Ca2+ absorption when dietary Ca intake is normal – => compensatory proteins • TRPV6 is critical for Ca2+ absorption when dietary Ca intake is low – Impaired intestinal Ca2t absorption in TRPV6 null mice on a low Ca diet - J Bone Miner Res 2007; 22: 274–285 - Endocrinology 2008; 149: 3196–3205 • Hypothesis: 1,25(OH)2D3 action not only affects transcellular but also paracellular Ca2+ transport • Regulate tight junction permeability in the intestine by modifying the expression of several tight junction proteins – Claudin-2 & claudin-12 - Mol Biol Cell 2008; 19: 1912–1921 • TRPV5 is definitely critical for renal Ca2+ reabsorption • TRPV5 null mice – Profound Ca2+ wasting – With compensatory increased intestinal Ca2+ absorption – Due to high 1,25(OH)2D3 serum levels, & normocalcemia as a result - J Clin Invest 2003; 112: 1906–1914 Direct effect of 1,25(OH)2D3 on bone homeostasis? • 1,25(OH)2D3 stimulate bone resorption – Increasing the expression of osteoclastogenic factors in osteoblasts • Receptor activator of nuclear factor kB ligand • 1,25(OH)2D3 -mediated signaling in regulating the activity of chondrocytes & osteoblasts – During endochondral bone formation & bone homeostasis • Aberrant growth plate development in VDR-deficient mice appears before the onset of hypocalcemia • High Ca diet corrected all aspects of the phenotype of CYP27B1-deficient mice, except long bone growth - Endocr Rev 2008;29: 726–776 • Mice lacking VDR expression in chondrocytes – Normal growth plate – But develop a transient phenotype of increased bone volume postnatally – Due to decreased expression of the angiogenic factor VEGF & the osteoclastogenic factor receptor activator of nuclear factor kB ligand in chondrocytes - J Clin Invest 2006; 116: 3150–3159 • 1,25(OH)2D3 -mediated signaling in chondrocytes • Necessary for timely vascular invasion & osteoclastogenesis during bone growth VITAMIN D & CANCER • Several large-scale epidemiological studies have shown an inverse correlation between exposure to sunlight (the major source of vitamin D) or vitamin D intake & risk of colorectal, breast, & prostate cancer Colorectal cancer risk • Am J Prev Med 2007; 32: 210–216 – Meta-analysis – 51% lower incidence of colorectal ca • Highest serum 25(OH)D3 quintile (82 nmol/l) compared to the lowest quintile (<=30 nmol/l) • Aliment Pharmacol Ther 2009; 30:113– 125 – Meta-analysis – Lower serum 25(OH)D3 inversely associated with colorectal cancer Am J Prev Med 2007; 32: 210–216 Am J Prev Med 2007; 32: 210–216 Aliment Pharmacol Ther 2009; 30:113–125 • NEJM 2006; 354: 684–696 – Randomized, double-blind, placebocontrolled trial involving 36,282 postmenopausal women from 40 Women’s Health Initiative centers, combined treatment of vitamin D3 (400 IU per day) & Ca – Not decrease colon cancer risk • Am J Clin Nutr 2007; 85: 1586–1591 – Much smaller RCT – 1100 IU per day of vitamin D3 + Ca – Decreased the overall cancer risk Am J Clin Nutr 2007; 85: 1586–1591 RR=0.232, P<0.005 RR=0.587, P=0.147 Breast cancer risk • Positive study in the US & Europe • Best Pract Res Clin Endocrinol Metab 2008; 22: 587–599 – UK – Women with 25(OH)D3 levels < 50nmol/l OR=3.54 for breast cancer risk compared with women with levels >50 nmol/l • Negative in other epidemiological studies Cancer Epidemiol Biomarkers Prev 2005; 14: 1991–1997 • Prostate cancer – Association with 25(OH)D3 status less clear than for colorectal cancer • Overall cancer outcome – Association remains ambiguous Am J Epidemiol 2009; 169: 1223–1232 • Supraphysiological doses of 1,25(OH)2D3 – Potent growth-inhibitory & prodifferentiating effects on a variety of cell types • VDR-/- mice hyperproliferation in the colon & mammary gland – Not develop cancer spontaneously but predisposed to cancer when challenged with carcinogenic agents • 1,25(OH)2D3 inhibits cell growth by hampering the transition from the G1 to the S phase of the cell cycle • 1,25(OH)2D3 accumulates cells in the G1 phase – Targeting cell-cycle regulators in a direct or indirect way • Cyclin-dependent kinase inhibitor p21(waf1/cip1) – Directly activated by 1,25(OH)2D3 – Through a vitamin D responsive element in its promoter region • Increase of cyclin-dependent kinase inhibitor p27(kip1) protein levels – Posttranslational modifications – 1,25(OH)2D3-induced repression of the miR181 family => accumulation of p27(kip1) • Decrease cyclin D1 & cyclin E expression • Decrease activity of complexes between cyclins & cyclindependent kinases – Influences the phosphorylation status of the retinoblastoma pocket protein family – Preventing the release of the E2F transcription factors 1, 2, 3 – Keeps the inhibitory complexes of E2F4 & E2F5 with p107 & p130 pocket proteins on the promoter of cell-cycle target genes Endocr Rev 2008;29: 726–776 • Presence of the VDR in tumors + growthregulatory effect of 1,25(OH)2D3 – Use of this compound in cancer prevention and/or treatment • Small trials – High weekly dose of 1,25(OH)2D3 instead of daily administration was safe & combination therapies were well tolerated ASCENT phase III clinical trial • • • • • Novacea, South San Francisco, CA, USA Large cohort of patients (950) Anrogenindependent prostate cancer Control arm: Taxotere every 3 weeks Weekly high dose of 1,25(OH)2D3 (DN101) + once-weekly Taxotere • Terminated 30 weeks earlier – Unexplained imbalance of deaths between the treatment & control group TX 522 • Inecalcitol; Hybrigenics, Paris, France • Structural analogs of 1,25(OH)2D3 • Clear dissociation between antiproliferative & calcemic effects • In phase II in patients with hormonerefractory prostate cancer TX 522 • Preliminary results – 27 of the 31 patients – Inecalcitol (at different doses up to 600 mg per day) & Taxotere during 18 weeks – Decrease in PSA levels >30% within 3 months of initiation of treatment – Without any changes in Ca parameters VITAMIN D AS IMMUNE MODULATOR • Exposure of skin to UVB => immunosuppression • Part of this effect is mediated through synthesis of vitamin D & activation to its active form 1,25(OH)2D3 under the influence of UVB • Receptors for vitamin D have been described in most cells of the immune system & many immune cells • Activate 25(OH)D3 to 1,25(OH)2D3 – Within the immune system a paracrine presence of 1,25(OH)2D3 Mol Aspects Med 2008; 29: 376–387 • Immune stimuli => immune cell => secretion of 1,25(OH)2D3 • Crucial immune stimulus: interferongamma • Other macrophage activators/differentiators simultaneously to activate a complex network of signaling pathways – LPS, phorbol myristate acetate, or TNF-α • TLR4 activation & TLR2/1 triggering – Able to induce 1α-hydroxylase in human macrophages – Induction of an antimicrobial response • 1,25(OH)2D3 -metabolizing enzyme, CYP24A1 – 24-hydroxylation – Expressed by antigen-presenting cells • 1,25(OH)2D3 enhanced capacity of innate antibacterial defense • More tolerogenic profile toward autoimmune phenomena • Dendritic cell (DC) & other APCs – Langerhans cells in skin – Central to the effect of vitamin D • Maturation, differentiation, & function of DCs affected, with downregulation of MHC class II & costimulatory molecules – CD40, CD80, & CD86 • => Tolerance-promoting phenotype • DC alterations + effects on cytokine secretion by the DC – Favoring IL10 & inhibiting IL12 • => T-cell function affected – Promoting development of Th2 lymphocytes within the CD4+ subset – Also affecting CD8+ CTL development T lymphocytes • Can be direct targets for 1,25(OH)2D3 – Inhibition of several cytokines, INF-r & IL-17 – Stimulation of others such as IL-4 • 1,25(OH)2D3 affects the expression of chemokine receptors on the surface of T lymphocytes – Determine the target tissue where any primed T lymphocytes will migrate to Regularory T cell • Tregs • 1,25(OH)2D3 has been shown to induce Tregs Semin Immunol 2004;16: 127–134 Monocyte/macrophage • Another important target cell of 1,25(OH)2D3 • TLR activation • Responsible for antibacterial & antiviral defenses • 1,25(OH)2D3 promote secretion of antibacterial products – Cathelicidin - Science 2006; 311:1770–1773 Vitamin D deficiency & autoimmunity • Epidemiological studies – Type 1 diabetes, multiple sclerosis, inflammatory bowel disease • Preclinical animal models – Vitamin D deficiency especially early in life enhances such autoimmune diseases • Need prospective intervention studies CARDIOVASCULAR & METABOLIC ACTIONS • Vitamin D-deficient rats or mice with deletion of VDR or 1α-hydroxylase – High renin hypertension with ultimately cardiac hypertrophy • Selective VDR deficiency in cardiac myocytes can reproduce the effects. • Am J Hypertens 2009; 22: 816 – Normotensive & hypertensive Caucasian, Hispanic, or African Americans – Lower serum 25(OH)D with higher BP • Endocr Rev 2008;29: 726–776 – Normotensive & hypertensive patients – BP inversely correlated with plasma 1,25(OH)2D & renin concentrations • Low 25(OH)D & metabolic syndrome – Obesity, insulin resistance, type 2 diabetes • Only very small scale intervention studies using vitamin D or its active hormone on BP or other aspects of the metabolic syndrome Endocr Rev 2008;29: 726–776 Endocr Rev 2008;29: 726–776 RENAL PROTECTION KI (2010) 77, 1000–1009; CLINICAL PERSPECTIVES • Major function of 1,25(OH)2D3 /VDR – Control the Ca & bone homeostasis • Combined presence of 25(OH)D3-1αhydroxylase + VDR in several nonclassical tissues introduced the concept of a paracrine/autocrine function for 1,25(OH)2D3 outside the Ca & bone metabolism. • 1,25(OH)2D3 capable of regulating cell differentiation & proliferation of normal (immune) cells & malignant cells • Poor vitamin D status is linked with all major diseases causing the majority of human morbidity – Cancer, immune diseases, metabolic syndrome, hypertension, & cardiovascular risk factors • The optimal daily dosage is highly debated • Most RCTs used 600–1000 IU of vitamin D3 per day – Decrease the risk of fractures & falls in the elderly • Serum 25(OH)D concentration – Should > 20 ng/ml (or 50 nmol/l) – Probably even 30 ng/ml (80 nmol/l) in patients with impaired renal function • Mean level of 25(OH)D around the world – ~ 20 ng/ml • US NHANES IV – < 30 ng/ml • Large part of the human population mildly vitamin D deficient • Patients with CKD have a greater than normal risk for bone diseases, cancer, immune disorders, & increased CV mortality • A number of observational studies have shown that treatment of hemodialysis patients with active vitamin D analogs decreases (cardiovascular) mortality. • Overall contribution of combined impaired 25(OH)D3–1,25(OH)2D3 status on morbidity & mortality in patients with CKD may be substantial but needs further RCTs. Endocr Rev 2008;29: 726–776 THANKS FOR YOUR LISTENING