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The most interesting news about
vitamin D for pharmacologists
LONDON 17.09.20111
AUTHOR: DR. ANNA DOROTHEA HÖCK
E-MAIL: [email protected]
Vitamin D: old and new insights
2
New
Old
UV-light
(320nm)
Nonclassical
actions
Skin
Liver
Kidney
1,25(OH)2D3
(active
metabolite)
Bone, bowel,
kidney,
parathyroid
London 18.09.2011
Local
CYP27B1
Genomic and
non-genomic
actions
25-OHD3
levels
measurable
The pleiotropic actions of vitamin D
3
 Genomic (via gene expression)
Pike JW, et al. Endocrinol Metab Clin North Am 2010;39(2):255-69
Pan YZ, et al. Drug Metab Dispos 2009;37(10):2112-7
Komagata S, et al. Mol Pharmcol 2009; 76(4):702-9
 Non-genomic (via cell-signaling)
Yu C, et al. Int J Biochem Cell Biol 2011;43(1):41-6
Shin JS, et al.
Zhao G, et al. Steroids 2010;75(8-9):555-9
Dixon KM, et al. J Steroid Mol Biol 2007;103(3-5):451-6
NEW:
Non-genomic actions seem to be necessary for
genomic actions
Ordonez-Moran, et al. Cell cycle 2009;8(11):1675-80
London 18.09.2011
Members of vitamin D endocrine system
4
Inactive? 25OHD3, active 1,25(OH)2D3, other vitamin D metabolites
Vitamin D activating (CYP27B1) and deactivating enzyme (CYP24)
Vitamin D-binding protein (VDB)
Vitamin D Receptor (VDR)
Calcium Receptor (CaR)
Transient receptor protein vanilloid type 1 and 6 (TRPV1,TRPV6)
Extracellular calcium (Cao), free cell calcium (Caic), protein bound calcium?,
Parathormone (PTH)
Parathormione related protein (PTHrP)
phosphate (free and bound?), putative phosphate receptor? (PhR)
Fibroblast Growth Factor 23 (FGF23/Klotho), and others (DMP1, PHEX, MEPE)
London 18.09.2011
Growing complexity of the vitamin D endocrine system
5
Synergism between
1,25(OH)2D3/VDR
and CaR
Ligand
independent
and promiscous
CaR
Ligand
independent
and promiscous
VDR actions
Theman TA, et al.
Curr Pharm Biotechnol
2009;10(3):289-301
London 18.09.2011
The activated CaR suppresses parathormone (PTH)
6
Well known:
Cao high, PTH low.
Less bone resorption.
Cao low, PTH high.
More bone resorption.
New:
(High Cao ), CaR active,
PTH repression active.
(Low Cao), CaR inactive(?),
PTH repression inactive(?)
Löffler G, Petrides PE, 8th edition, Springer, Germany
London 18.09.2011
The promiscous calcium Receptor (CaR)
7
The CaR is activated not only by calcium,
but also by
other di-, tri- and even multivalent ions,
for instance spermine and aminoglycoside antibiotics,
ionic strength, amino acids,
and many pharmacological compounds
Thus, CaR is an osmoreceptor and uses all these compounds to
become activated in case of sub-threshold concentrations of Ca2+o
Riccardi D. Downloaded from Exp Physiol (ep.physoc.org) 2010;
London 18.09.2011
The differential actions of CaR in malignancy
8
CaR can be an oncogene (eg. in highly malignant breast and some
prostate cancers)
CaR can be a tumor suppressor (colon and parathyroid cancers)
Important: Ca2+o while acting on CaR promotes the expression of Ecadherin in several carcinoma cell lines
E-cadherin interacts with beta-catenin (a proto-oncogene)
The complex E-cadherin/beta-catenin on cell surface promotes cell
cohesion (= proto-oncogene bound)
Saidak Z, et al. Endocrine Reviews 2009; 30(2):178-195.
London 18.09.2011
Like CaR, VDR is also promiscuous with regard to activating ligands
9
Bile acids
Wolf G.
Nutr Rev 2002;60(9):281-3.
AT1-blocker (sartanes)
Agarwal R.
Kidney Int 2010;77(11):1000-9.
25OHD3 ????
Lou YR, et al. J Steroid Biochem Mol
Biol 2004;92(4):317-25.
London 18.09.2011
What can be read between the lines?
10
Derived from the lessons about
vitamin D analogs and from
pharmacological research in
general:
Different ligands exert
differential effects on gene
expression, even if the
same receptor is targeted.
London 18.09.2011
The complexity of calcium
metabolism
11
KNOWN
AND IMAGINABLE
CONSEQUENCES
OF CALCIUM DEFICIENCY
London 18.09.2011
Calcium and phosphate regulating organs
12
The aim:
tight
control of
calcium
and
phosphate
stores
• Bone
• Bowel
• Kidney
• Parathyroid gland
Löffler G, Petrides PE, 8th edition, Springer, Germany
London 18.09.2011
Vitamin D deficiency results in disturbed function of TRP channels in
bowel and kidney
13
That
leads not
only to
deficiency
of
calcium
London 18.09.2011
• but as well to deficiency of
other minerals (K+, Mg 2+),
and probably of phosphate
• There is mutual induction of
the deficiencies
Hsu YJ, et al. Biochem Biophys Acta 2007; 1772(8):928-36.
Ghose RR, et al. Postgrad Med J 1980;56(661):785-6.
A renal tubular damage develops in vitamin D depletion
14
Fanconi syndrome Type I-like disorder with renal
phosphate wasting, very similar to XLH, however
combined with acidosis, glycosuria, aminaciduria,
and renal loss of calcium, magnesium and potassium
Phosphate loss and acidosis contribute to bone loss
Drezner MK. In: Vitamin D. Feldman et al; eds. 2005
London 18.09.2011
Clinical symptoms of phosphate deficiency
15
Fatigue and muscle weakness (ATP deficiency)
Mental and psychiatric abnormalities
Neurologic and neuromuscular abnormalities
Bone pain and osteomalacia with pseudofractures
Impaired oxidative phosporylation, enhanced glycolysis
Organ dysfunction (heart, lung, kidney)
Microspherocytosis, hemolysis, reduced dissociation of oxyhemoglobin,
Impaired chemotaxis, phagocytosis, bacterial killing, and platelet dysfunction
Harrison‘s Principles of Medicine. 17th edition.
London 18.09.2011
Symptoms of calcium deficiency are very similar
16
Mental and psychiatric abnormalities (irritability, depression, psychosis)
Neurologic and neuromuscular abnormalities (muscle, laryngeal, carpopedal spasms,
convulsions, tetany, facial grimacing)
Intestinal cramps and malabsorption
Increased intracranial pressure
Respiratory arrest
QT prolongation, cardiac arrhythmia
Harrison‘s Principles of Medicine. 17th edition.
London 18.09.2011
Symptoms of magnesium deficiency also similar
17
Depression, psychosis
Neuromuscular dysfunction (tetany, tremor, seizures,
muscle weakness, ataxia, nystagmus, vertigo)
Apathy
Delirium
Harrison‘s Principles of Medicine. 17th edition.
London 18.09.2011
A special feature of magnesium deficiency
18
Blunted PTH response
(reduced glandular
secretion and hormone
resistance)
Sahota O, et al. Osteoporos Int 2006; 17(7): 1013-21.
London 18.09.2011
A possible link between calcium deficiency and inflammation
19
Low calcium stores
High calcium Stores
 Bone resorption is
 Strong innate immune
hyperactive (a
proinflammatory
event).
system and regulated,
modulated and
mitigated adaptive
immune system.
Fleet JC. J Musculoskelet Neuronal
Interact 2006:6(4):336-7.
Panda DK, et al. PNAS 2001;89:74987503.
Peterlik M, et al. Eur J Clin Invest
2005;35(5):290-304.
London 18.09.2011
What means calcium deficiency for whole body and for cells?
20
Whole body response:
• To maintain a physiologic
calcium gradient between
extra- and intracellular
compartments,
bone calcium must be
dissolved,
that means loss
of bone
(calcium, phosphate),
and paradoxical mineral
overflow leading to
HYPERCALCEMIA
London 18.09.2011
Possible cellular
response:
• Less calcium storing
proteins?
• Less calcium
dependent proteins?
• Increased ratio of
free calcium to
protein bound calcium?
Cadherin superfamily
21
London 18.09.2011
Cadherin with Calcium and without
22
London 18.09.2011
Role of calcium in muscle
23
Vortrag in Bergisch-Gladbach 10/2011
Ca/Tropomyosin enables muscle contraction
24
London 18.09.2011
25
Role of calcium in nerve signaling
Vortrag in Bergisch-Gladbach 10/2011
Vitamin D and calcium act cooperatively
26
Pro calcium-authors:
Bikle DD,
Peterlik M,
Grant WB,
Cross HS,
Thys-Jacobs S,
Heaney RP
London 18.09.2011
The reluctance with highly warranted clinical studies
27
There is not yet a study combining adequate vitamin
D dosages of at least 2000 IU (50mcg), given along
with differential calcium doses to document the
calcium needs of the body in various disease
conditions.
Not only acquired diseases, but also inborne diseases
might be complicated by deficiency of vitamin D and
calcium.
London 18.09.2011
The pleiotropic organ
protection of vitamin D
28
1. IMMUNE SYSTEM
2. REDOX SYSTEM
3. EFFECTS ON MITOCHONDRIA
4. EFFECTS ON HEART AND KIDNEY
5. EFFECTS ON AMINO ACIDS AND
POLYAMINES
6. EFFECTS ON BRAIN
7. AUTORADIOGRAPHIC VITAMIN D TARGETS
London 18.09.2011
Some treatment effects of vitamin D are known since long time
29
New
Old
UV-light is beneficial to
tuberculosis
Ryberg Finson 1903
Vitamin D induces
cathelicidin (natural
microbe antagonist)
Liu 2006
Vitamin D treatment
ameliorates psychiatric
manifestations
Vitamin D deficiency
results in chronic
fatigue
Gilmour A. School Hygiene 1912; 9:6-16.
Hallerhan MM. Arch Psychol 1938;229:1-67.
Hoeck 1997,2000,2011
London 18.09.2011
Effects of vitamin D
on immune system
30
ENHANCES INNATE IMMUNE
SYSTEM
REGULATES AND MODULATES
ADAPTIVE IMMUNE SYSTEM
London 18.09.2011
Vitamin D regulated cells of the immune system
31
Macrophages and Natural killer cells (NK-cells)
Nelson CD, et al. PLoS One 2010;5(11):e15469.
T-cells (NKT cells and CD8 alpha T cells, and effector T cell cytokines, switch from TH1/Th17
to Th2/Treg profile)
Cantorna MT. Ann N Y Acad Sci 2011;1217:77-82.
Guillot X, et al. Joint Bone Spine 2010;77(6);552-7.
B-cells (I epsilon, a prerequisite for IgE production is transrepressed by 1,25(OH)2D3)
Milanovic M, et al. J Allergy Clin Immunol 2010;126(5):1016-23.
Dendritic cells and macrophages (antigen presenting cells)
Adams JS, et al. Ann N Y Acad Sci 2007;1117:94-105.
Dermal mast cells (protection against UV-B radiation)
Yu C, et al. Int J Biochem Cell Biol 2011;43(1):41-6.
London 18.09.2011
A major topic: antimicrobial action of vitamin D
32
IL-17A enhances vitamin D3-induced expression of cathelicidin
antimicrobial peptide in human keratinocytes.
Peric M, et al. J Ommunol 2008;181:8504-12.
„Th17 cells are a new lineage of CD4+Th cells.
They produce proinflammatory cytokines
(IL-17, IL-22) in a 1,25(OH)2D3 dependent mechanism.“
„Cathelicidins do not only kill microbes, but modulate
immune functions. They stimulate cytokine release,
chemotaxis, angiogenesis, and wound repair.“
London 18.09.2011
Other important findings about microbe defense
33
IL-15 links TLR2/1-induced macrophage differentiation to the
vitamin D-dependent antimicrobial pathway.
Krutzig S, et al. J Immunol 2008; 181(10):7115-20.
Vitamin D-directed rheostatic regulation of monocyte
antibacterial response.
Adams JS, et al. J Immunol 2009;182:4289-95.
Role of autophagy in the host response to microbial infection and
potential for therapy.
Fabri M, et al. Current Opinion in Immunology 2010;23:1-6.
London 18.09.2011
1,25(OH)2D3 and IL-2 work together
34
1,25-dihydroxyvitamin D3 and interleukin-2 combine to inhibit
T cell production of inflammatory cytokines and promote
development of regulatory T cells expressing CTLA-4 and FoxP3
Jeffery LE, et al. J Immunol 2009;183(9):5458-67.
„Stimulation of CD4+CD25-T cells in presence of 1,25(OH)2D3
inhibited production of proinflammatory cytokines
(IFN-gamma, Il-17, Il-21).
Additionally, 1,25(OH)2D3 stimulated expression of high levels
of CTAL-4 and FoxP.
FoxP expression required the presence of Il-2.
These cells showed characteristics of regulatory T-cells.“
London 18.09.2011
Modified VDB treatment against infections and cancer?
35
VDB-Protein is a multifunctional protein:
Binding of vitamin D metabolites
Globular actin scavenging
Prevention of actin polymerization
Binding of FFA
Interactions with macrophages and
complement
Bogaerts I, et al. In: Vitamin D. Feldman et al; eds. 2005.
London 18.09.2011
Vitamin D against drug company‘s crisis?
36
Vitamin D and calcium substitution
might become a new standard for nearly any
disease,
in particular when treating with biologicals
„Serum 25HD3 should be measured in case of secondary
hyperparathyroidismus, and in case of insufficiency, treated as part of any
management course.“
Eastell R, ez al. J Endocrinol Metab 2009;94(2):340-50.
„Vitamin D status in kidney transplants patients:
need for intensified routine supplementation.“
Ewers B, et al. Am J Clin Nutr 2008;87:431-7.
London 18.09.2011
Effects of vitamin D on redoxsystem
37
REDUCES OXIDATIVE STRESS
REDUCES REDUCTIVE STRESS
London 18.09.2011
Vitamin D acts as a stress reducing agent
38
„Protection against cellular stress by 25-hydroxyvitamin D3 in breast
epithelial cells. „
Peng X, et al. J Cell Biochem 2010;110(6):1324-33.
„Vitamin D and the cellular response to oxidative stress“
Koren R et al. In: Vitamin D. Feldman ed. 2005.
„Thioredoxin-1 and its natural inhibitor, vitamin D3 upregulated protein,
are differentially regulated by PPARalpha in human macrophages“
Billiet L, et al, J Mol Biol 2008;384(3):564-76.
„Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative
stress in non-malignant human prostate epithelial cells“
Bao BY. Et al. Int J Cancer 2008;122(12):2699-706.
London 18.09.2011
Effects of vitamin D on
mitochondria
39
MITOCHONDRIA
AS A POSSIBLE MAJOR LINK
BETWEEN
VITAMIN D DEFICIENCY AND
ENERGY DEFICIENCY (FATIGUE)?
London 18.09.2011
Rare publications about vitamin D and mitochondria
40
„Molecular mechanisms involved in the
enhancement of mitochondrial malate
dehydrogenase activity by calcitriol in chick
intestine“
Perez A, et al. J Nutr Biochem 2010;21(12):1232-7.
„Involvement of the vitamin D receptor in energy
metabolism: regulation of uncoupling proteins“
(influence on beta-oxidation and UCP-expression)
Wong KE, et al. Am J Physiol Endocrinol Metab 2009;296(4):E820-8.
London 18.09.2011
Effects of vitamin D on amino
acid and polyamine synthesis
41
MOST PUBLICATIONS NOW
OUTDATED.
A FORGOTTEN ISSUE.
London 18.09.2011
Organ protection of heart and kidney
42
Anti-inflammatation
and antifibrosis
Suppresion of reninangiotensonaldosterone system
Prevention of insulin
resistence
Prevention of
secondary
hyperparathyroidism
Suppression of atrial
natriuretic peptide
Regulation of
smooth muscle cell
proliferation
Regulation of
thrombosis and
fibrinolysis (PAI1
suppression)
London 18.09.2011
Vessel relaxation
Cozzoli M, et al. Eur J Heart Fail
2010;12(10):1031-41.
Wu-Wong JR, et al. Curr Opin Investig
Drugs 2006; 7(3):206-13.
Organ protection of nervous system
43
Vitamin D as a neuroactive substance: review.
Kiraly SJ, et al. ScientificWorldJournal 2006;26(6):125-39.
Blood biomarkers of osteoporosis in mild cognitive impairment and Alzheimer‘s disease.
Luckhaus C, et al. J Neural Transm 2009;116(7):905-11.
Vitamin D3 signaling in the brain enhances the function of phosphoprotein enriched in
astrocytes—15kD (PEA-15)
Obradovic D, er al. J Cell Mol Med 2009;13(9B):3315-28.
Vitamin D, light and mental health.
Humble MB. J Photochem Photobiol b 2010;101(2):142-9.
Relationship between vitamin D levels and depressive symptoms in older residents from a
national survey population.
Stewart R, et al. Psychosom Med 2010;72(7):608-12.
London 18.09.2011
Further confirmative publications:
44
Low serum levels of 25-hydroxyvitamin D (25-OHD)
among psychiatric out-patients in Sweden: relations with
season, age, ethnic origin and psychiatric diagnosis.
Humble MB, et al. J Steroid Biochem Mol Biol 2010;121(1-2):467-70.
Metabolic and endocrine factors in mild
cognitive impairment.
Etgen T, et al. Ageing Res Rev 2010;9(3):280-8.
London 18.09.2011
However: there still exists some controversy
45
Vitamin D and depression.
Howland RH. J Psychosoc Nurs Ment Health Serv 2011;49(2):15-8.
Criticism: Review. He points to the bad quality of the cited studies.
Calcium and vitamin D intakes may be positively associated with
brain lesions in depressed and nondepressed elders.
Payne ME, et al. Nutr Res 2008;28(5):285-92.
Criticsm: mean intake of vitamin D3: 341 IU/d
Diffuse musculoskeletal pain is not associated with low
vitamin D levels or improved by treatment with vitamin D.
Warner AE, et al. J Clin Rheumatol 2008;14(1):12-6.
Criticism: 50,000 IU Ergocalciferol/week
London 18.09.2011
Vitamin D and muscle function
46
VITAMIN D STATUS AND MUSCLE
STRENGTH CORRELATE POSITIVELY.
HOWEVER:
FURTHER STUDIES ARE NEEDED AND
THE MECHANISMS OF ACTION MUST
BECOME CLEARER.
London 18.09.2011
Muscle weakness due to atrophy of type II fibres?
47
„An overview of sarcopenia and numbers on prevalence and
clinical impact“
Von Haehling S, et al. J Cachex Sarcopenia Muscle 2010;1(2):129-33.
„denervation of motor units and net conversion of fast type II
muscle fibers to slow type I fibers in the elderly over 50“
In vitamin D depletion type II fibers are
atrophic!
Glerup H. Muscles and falls. In: Vitamin D. Feldman et al, eds. 2005.
London 18.09.2011
However: The hypothesis of Walter E Stumpf:
48
„There are no detectable VDRs in
muscle by micro-autoradiography,
but the muscle-motor-nerve unit
of the motoneuons is disturbed
by vitamin D depletion."
(Personal communication)
London 18.09.2011
VDR detection by Walter E Stumpf:
49
„Vital cell functions: proliferation, differentiation, secretion.
Strong autoradiographic binding found in:
skin epidermis, hair follicles, sebaceous and sweat glands,
myoepthelial cells, certain brain and spinal cord neurons, specific cells
in anterior (esp. thyr0tropes) and posterior pituitary, thymus reticular
cells, adrenal medullary cells, stomach gland isthmus cells, enteroendocrine cells, pyloric muscle cells, pancreas beta cells, heart atrial
myocytes, special cells in salivary glands, all population in female and
male reproductive organs, liver sinus littoral cells, perhaps Ito cells. „
Stumpf WE. Europ J Drug Metab Pharmacokin 2007, 2008. www:walterstumpf.com
VDRs not found in:
„muscle nuclei and fat cells, not at plasma membranes, however found
in ground substance of mucosa.“
However: „such negative findings do not exclude possible actions
under certain conditions, which point to the merits of further study.“
London 18.09.2011
Some well known vitamim D target genes
50
Enhanced expression
24-hydroxylase
calbindin
osteocalcin
osteopontin
p21 Ras
beta3-integrin
vitamin D receptor
Löffler G, Petrides PE. 8th edition, Springer , Germany
London 18.09.2011
Repressed expression
1-alpha-hydroxylase
parathormone
collagen 1
c-myc
interleukin-2
calcitonin
The initial health problems
due to vitamin D deficiency
51
Fatigue
London 18.09.2011
Functional
disorder
Pains
Later on:
well
defined
diseases
Diseases attributed to vitamin D depletion
52
Cardiovascular (heart insufficiency, hypertension)
Pulmonary (COPD, asthma, recurrent infections, CFTR)
Kidney (fibrosis, renal tubular acidosis)
Autoimmunity (eg. MS, rheumatoid arthritis, thyroid disease, biliary cirrhosis)
Chronic inflammation (inflammatory bowel)
Cancer (colon, breast, prostate)
EBV (VDR-resistance!), lymphoma,
Connective tissue (scleroderma, Sjögren syndrome)
Degeneration (osteoarthritis)
London 18.09.2011
Vitamin D targets maintain homeostasis
53
Metabolic and energy system with mitochondria
Immune and stress system
Nervous system
Endocrine system
Muskuloskeletal system
Cardiovascular system
Transport systems with exchange, absorption, reabsorption, excretion and detoxification
Cell cycle, proliferation, differentiation, apoptosis
Cell signalling
Tissue structure and tissue-cell crosstalk
London 18.09.2011
The controversy about the optimal 25OHD3 level
54
30 ng/ml
= 80 nMol/L
(Vieth R, Lips P, Heaney RP, Grant
WB, Giovannucci E, Hollis BW,
Hollick MF, Norman AW, many
others)
40 ng/ml
= 100 nMol/L
(Grant WB, Pro Biophy Mol Biol
2009)
However not willing that
95% of the population are
declared as in health risk,
and therfore correcting
the desired 25OHD3 level
down to 20 ng/ml (50
nMol/L):
London 18.09.2011
60 – 80 ng/ml
= 150 – 200 nMol/L
(Gominak S, Garland CF)
IARC
and IOM
The optimal vitamin D dose
55
2000 IU = 50 mcg/day (upper limit of daily allowance NHI)
4000 IU = 100 mcg/day reached a steady state (over 3 months)
Vieth R
5,000 to 10,000 IU?
Initially 40,000 to 100,000 IU/d (record of Dr. von
Helden, Vitamin D Research Group, Germany)
London 18.09.2011
Calcium treatment pitfall:
56
Severe calcium
deficiency with
paradoxical
hypercalciuria
Severe phosphate
deficiency with
hypercalciuria
Altered set point
of CaR?
Renal tubular
acidosis?
London 18.09.2011
Vitamin D resistance due to chronic
inflammation?
57
An inhibitory effect of TNF alpha on VDR action
results in diminished responsiveness to 1,25(OH)2D3 in
osteoporosis and inflammatory arthritis.
„There is now evidence that this effect may be partly
mediated by activation of NFkB.
Effect not mediated by inhibition of VDR binding to DNA,
but by interference with coactivator complexes and
polymerase II preinitiator complex.“
Farmer PK, et al. Am J Physiol Endocrinol Metab 2000; 279(1):E213-20.
London 18.09.2011
Vitamin D resistance due to chronic pathogens?
58
Epstein-Barr virus encoded
EBNA-3 binds to vitamin D
receptor and blocks activation of
ist target genes.
Cell Mol Life Sci
2010;67(24):4249-56.
London 18.09.2011
Your take-home-messages
59
The complexitiy of vitamin D endocrine system is not yet fully
understood and so far as yet known, not easily understandable
All important organ and functional systems depend on vitamin D
Compromised vitamin D efficiency is reported due to:
calcium deficits
chronic inflammation
chronic pathogens (EBV, other pathogens as well?)
London 18.09.2011