PATHOPHYSIOLOGICAL ASPECTS OF
CALCIUM AND PHOSPHATES
HOMEOSTASIS. BONE PATHOPHYSIOLOGY
November 29, 2016
CALCIUM
 In all eukaryotic cells, the cytosolic concentration of
calcium ions ([Ca2+]c) is tightly controlled by complex
interactions among transporters, pumps, channels and
binding proteins. Finely tuned changes in [Ca2+]c
modulate a variety of intracellular functions, and
disruption of Ca2+ handling leads to cell death.
 Despite the importance of Ca2+ in physiology and
pathology, the number of known genetic diseases that
can be attributed to defects in proteins directly
involved in Ca2+ homeostasis is limited to few
examples. This paucity in contrast with the wide
molecular repertoire may depend on the extreme
severity of the phenotype (leading to death in utero)
or, conversely, on functional compensation due to
redundancy. In the latter case, it stands to reason that
other genetic defects in calcium signaling have yet to
be identified owing to their subtle phenotype.
CALCIUM HOMEOSTASIS
 Intracellular
 Extracellular
Intracelullar calcium homeostasis
ALTERED CELLULAR CALCIUM HOMEOSTASIS
Bazal
Ca++i
Response of
Ca++i on
stimulation
Example Type
Gradually
increasing
=/ MI, toxin-induced cell
death, acute pancreatitis
Acute
Increased,
stabile
 Hypertension Chronic
 Idiopathic heart failure Chronic
Normal,
stabile
 Alzheimer´s disease Chronic
 Chronic inflammatory
diseases (M. Crohn, RA)
Chronic
SYSTEMIC CALCIUM HOMEOSTASIS
 Systemic calcium homeostasis is critical to the survival of
multicellular organisms, and complex, inter-dependent regulatory
systems have evolved to maintain Ca2+ in the extracellular fluid
within a narrow range (1.1–1.4 mM Ca2+ for humans).
 The calcium sensing receptor, CaR, is exquisitely sensitive to small
changes in Ca2+ . In parathyroid chief cells, this permits sensing of
minute fluctuations in Ca2+ (±200 μM) with increases in Ca2+
causing decreases in parathyroid hormone (PTH) secretion.
 PTH has effects on the kidney to increase Ca2+ reabsorption from
the filtrate and synthesis of vitamin D, 1,25(OH)2D (which
enhances intestinal absorption of Ca2+), and on bone to increase
release of Ca2+ and phosphate by demineralization. Recent
reviews detail the mechanisms involved in systemic calcium
homeostasis and the pathologies resulting from their
dysregulation).
 CaR is also expressed in many cell types which are not directly
involved in systemic calcium homeostasis, including neurons and
glia, endocrine and exocrine glands, epithelia, cells of
hematopoietic origin, and keratinocytes.
BODY DISTRIBUTION OF CALCIUM
AND PHOSPHATE
 There are three major pools of calcium in the
body:
 Intracellular calcium: A large majority of
calcium within cells is sequestered in
mitochondria and endoplasmic reticulum.
Intracellular free calcium concentrations
fluctuate greatly, from roughly 100 nM to
greater than 1 M, due to release from
cellular stores or influx from extracellular fluid.
These fluctuations are integral to calcium's
role in intracellular signaling, enzyme
activation and muscle contractions.
BODY DISTRIBUTION OF CALCIUM
AND PHOSPHATE
 Calcium in blood and extracellular fluid: Roughly
half of the calcium in blood is bound to proteins. The
concentration of ionized calcium in this
compartment is normally almost invariant at
approximately 1 mM, or 10,000 times the basal
concentration of free calcium within cells. Also, the
concentration of phosphorus in blood is essentially
identical to that of calcium.
 Bone calcium: A vast majority of body calcium is in
bone. Within bone, 99% of the calcium is tied up in
the mineral phase, but the remaining 1% is in a pool
that can rapidly exchange with extracellular
calcium. As with calcium, the majority of body
phosphate (approximately 85%) is present in the
mineral phase of bone. The remainder of body
phosphate is present in a variety of inorganic and
organic compounds distributed within both
intracellular and extracellular compartments.
THE MOLECULAR ACTORS OF CALCIUM SIGNALING
 Calcium ions are the most common second messengers of eukaryotic
cells, decoding the information conveyed by a variety of extracellular
molecules that do not cross the plasma membrane (hormones,
neurotransmitters, growth factors) into widely diverse intracellular effects
(for example, muscle contraction, oocyte fertilization, endocrine or
exocrine secretion, cell proliferation or death).
 For this purpose, all cells finely tune Ca2+ signals using a ubiquitous, broad
group of gene products: pumps, channels, transporters and binding
proteins.
 The Ca2+ signal then impinges on a number of (directly or indirectly)
Ca2+-sensitive enzymes that convert changes in Ca2+ concentration into
defined cell actions.
 Given the steep electrochemical gradient between the outside world (or
the intracellular stores) and the cytoplasm, increases in [Ca2+]c can be
elicited by both Ca2+ release from intracellular stores and Ca2+ influx
through plasma membrane channels
 The relative importance of Ca2+ influx versus Ca2+ mobilization depends
on the stimulus and the cell type.
MOBILIZATION OF CA2+
 Mobilization of Ca2+ from intracellular organelles is also a ubiquitous
mechanism for increasing [Ca2+]c. This process is highly specialized in
striated (cardiac and skeletal) muscle.
 In other cells, including neurons, the primary route for Ca2+ mobilization is
most often that initiated by the stimulation of G protein– or
phosphotyrosine-coupled receptors of the plasma membrane, which
activate different isoforms of phospholipase C. In turn, this enzyme
hydrolyzes the plasma membrane lipid phosphatidylinositol 4,5bisphosphate
into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. IP3
interacts with Ca2+ channels localized in the ER1,2 and Golgi apparatus4
(the IP3 receptors (IP3Rs) occur in three isoforms), causing them to open
and release Ca2+ into the cytosol. In many cells, the IP3R then synergizes
with other intracellular channels operated by different second
messengers; for example, nicotinamide adenine dinucleotide acts on an
unknown target, and cyclic ADP ribose acts on all three isoforms of
ryanodine receptors (RyRs), albeit at higher concentrations on type 1.
Ca2+ release through RyRs can be directly triggered by Ca2+ itself (as
well established incardiac cells), or IP3 can be produced by more
unusual routes, such as through cAMP-activated phospholipase Cε5.
 Ca2+ release from intracellular stores is most often accompanied by
Ca2+ influx through plasma membrane channels, and the mechanism by
which these open is still debated.
 The Ca2+ signal is terminated by the combined activities of the Ca2+
extrusion mechanisms (the plasma membrane Ca2+ ATPase (PMCA) and
the Na+/Ca2+ exchanger (NCX)) or the sarcoendoplasmic reticulum
Ca2+ ATPase (SERCA) that reaccumulates the cation in the ER lumen.
CA2+ SIGNALING
 But Ca2+ signaling is frequently implicated in the
pathophysiological process of common multifactorial diseases
with a genetic basis (for example, neurodegenerative diseases,
including Alzheimer dementia and Huntington disease, ischemia,
demyelinating and autoimmune disorders, cardiac hypertrophy
and others).
 Of particular interest, presenilin-1 and -2, mutated in early-onset
familial Alzheimer disease, can modulate in neurons and
heterologous expression systems the kinetics of ER Ca2+ release
through the IP3R and the ensuing process of capacitative Ca2+
entry. The molecular basis of this alteration is unclear.
 Moreover, Ca2+ signals are involved in the modulation of the
apoptotic process, and Ca2+ dysregulation is also associated with
death by necrosis. Ca2+ signals regulate both the metabolic
activity of mitochondria and their release of pro-apoptotic
factors.
THE CA2+-PERMEABLE CHANNELS
 The Ca2+-permeable channels of the plasma
membrane are traditionally grouped into three
different families:
 (1) voltage-operated Ca2+ channels (Cav),
whose opening probability is increased by
decreases in membrane potential (the
traditional nomenclature of the currents, L, N, T,
P/Q and R subtypes) is based on their
functional properties, pharmacological
sensitivity or cellular expression and reflects the
different nature of the pore-forming subunit.
THE CA2+-PERMEABLE CHANNELS
 (2) receptor-operated Ca2+ channels, also referred to as
ligand-gated channels, whose opening probability is
increased by binding of a ligand to the channels
themselves;
 (3) second messenger–operated channels, whose
opening probability is controlled by the binding of a
second messenger on the inner surface of the membrane.
 The TRP (transient receptor potential) family includes the
channels responsible for the Ca2+ entry triggered by the
agonist-dependent release of Ca2+ from the endoplasmic
reticulum (ER). The various members of the TRP family have
distinct gating mechanisms (second messengers,
extracellular ligands, osmotic or mechanical stress,
depletion of intracellular stores and, in a few cases,
unknown). These ion channels, like many others, are homoor
heteromultimer protein complexes in which one subunit
is principally responsible for forming the channel pore and
the other subunits have a modulatory role. They are
polymodal sensory ion channels as they integrate multiple
physical and chemical stimuli including heat, pH, and
lipids.
Scheme of an idealized mammalian cell with the localization of
the main players of Ca2+ homeostasis. PM Ca2+ channels, generic plasma
membrane Ca2+ channels (voltage-, ligand- or second messenger–operated);
GPCR, G protein–coupled receptor; PLC, phospholipase C; PIP2,
phosphatidylinositol 4,5 bisphosphate; DAG, diacylglycerol; GFR, growth
factor receptor; ATP2C1, Golgi-resident Ca2+ ATPase; cADPR, cyclic ADP
ribose; CICR, Ca2+ induced Ca2+ release; Mt, mitochondrion.
CALCIUM SENSOR
The calcium sensor is expressed in a broad range of cells,
including parathyroid cells and C cells in the thyroid
gland, indicating its involvement in controlling the
synthesis and secretion of parathyroid hormone and
calcitonin. The calcium sensor directly affects secretion
of these two hormones.
The calcium sensor is also expressed in several cell types
in the kidney, osteoblasts, a variety of hematopoietic
cells in bone marrow, and in the gastrointestinal
mucosa.
Such a broad distribution of expression supports that
concept that calcium, acting as a hormone, has direct
effects on the function of many cell types.
THE EXTRACELLULAR CALCIUM-SENSING RECEPTOR
(CaR)
 The calcium-sensing receptor is a
member of the G protein-coupled
receptor family. Like other family
members, it contains seven
hydrophobic helices that anchor it in
the plasma membrane.
 The large (~600 amino acids)
extracellular domain is known to be
critical to interactions with extracellular
calcium. The receptor also has a rather
large (~200 amino acids) cytosolic tail.
These features are depicted in the
figure to the right; the red highlights on
the intracellular domain correspond to
potential protein kinase
phosphorylation sites.
store-operated
Ca2+ entry channels
G protein–coupled receptor
TO THE PREVIOUS PICTURE
 Molecular players in CaR-mediated autocrine/paracrine
integration of Ca2+-mediated signaling. Agonist activation of a
Ca2+-mobilizing GPCR (1) activates heterotrimeric G protein Gq
(2), leading to activation of phospholipase Cβ (PLCβ) (3), and
generation of inositol 1,4,5-trisphosphate (InsP3), which binds to
the endoplasmic reticulum-localized inositol trisphosphate
receptor (IP3R) (4), inducing release of Ca2+ into the cytosol. Most
of the Ca2+ released from the endoplasmic reticulum is pumped
out of the cell by the plasma membrane-localized Ca2+ ATPase
(PMCA) (5). Restitution of endoplasmic reticulum Ca2+ content
occurs via store-operated Ca2+ entry channels (SOCE) (6) and
the sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) (7). If the
activated cell also expresses the calcium sensing receptor (CaR),
potentiation of the response is possible, as PMCA pumps Ca2+ out
of the cell into a restricted diffusion space, significantly increasing
the [Ca2+] extracellulary, leading to CaR activation (8).
TO THE PREVIOUS PICTURE
 Potential mechanism for CaR-mediated integration of
Ca2+ signaling. When a single cell (or a few cells) in a
multicellular network is (are) activated by an agonist
for a Ca2+-mobilizing GPCR, Cai2+ increases, and is
pumped out of the cell via PMCA.
 The local increase in [Ca2+] in the restricted diffusion
space surrounding the cells potentiates the activity in
the agonist-activated cell (autocrine activation), and
also activates CaR on adjacent cells (paracrine
activation).
 CaR activation increases intracellular Ca2+, leading to
PMCA-mediated Ca2+ efflux in adjacent cells,
propagating the Ca2+ signaling response through the
tissue. In this example, CaR is present in proximity to
PMCA, which has been observed in epithelial tissue.
FLUXES OF CALCIUM AND PHOSPHATE
Two main tasks for regulation:
 Ca x HPO4- product in blood = constant (!!!)
 Normal levels of calcium and phosphates at the same
time are necessary
FLUXES OF CALCIUM AND PHOSPHATE
 Maintaining constant concentrations of calcium in blood
requires frequent adjustments, which can be described as fluxes
of calcium between blood and other body compartments.
 Three organs participate in supplying calcium to blood and
removing it from blood when necessary:
 The small intestine is the site where dietary calcium is absorbed.
Importantly, efficient absorption of calcium in the small intestine
is dependent on expression of a calcium-binding protein in
epithelial cells.
 Bone serves as a vast reservoir of calcium. Stimulating net
resorption of bone mineral releases calcium and phosphate into
blood, and suppressing this effect allows calcium to be
deposited in bone.
 The kidney is critically important in calcium homeostasis. Under
normal blood calcium concentrations, almost all of the calcium
that enters glomerular filtrate is reabsorbed from the tubular
system back into blood, which preserves blood calcium levels. If
tubular reabsorption of calcium decreases, calcium is lost by
excretion into urine.
CALCIUM DEFICIENCY IN BLOOD
CALCIUM OVERLOAD IN BLOOD
Calcium Deprivation Calcium Loading
Parathyroid hormone Secretion stimulated Secretion inhibited
Vitamin D
Production stimulated by increased
parathyroid hormone secretion
Synthesis suppressed due to low parathyroid hormone
secretion
Calcitonin Very low level secretion Secretion stimulated by high blood calcium
Intestinal absorption of calcium
Enhanced due to activity of vitamin D on
intestinal epithelial cells
Low basal uptake
Release of calcium and phosphate
from bone
Stimulated by increased parathyroid hormone
and vitamin D
Decreased due to low parathyroid hormone and
vitamin D
Renal excretion of calcium
Decreased due to enhanced tubular
reabsorption stimulated by elevated
parathyroid hormone and vitamin D;
hypocalcemia also activates calcium sensors
in loop of Henle to directly facilitate calcium
reabsorption
Elevated due to decreased parathyroid hormonestimulated
reabsorption.
Renal excretion of phosphate
Strongly stimulated by parathyroid hormone;
this phosphaturic activity prevents adverse
effects of elevated phosphate from bone
resorption
Decreased due to hypoparathyroidism
General Response
Typically see near normal serum
concentrations of calcium and phosphate due
to compensatory mechanisms. Long term
Low intestinal absorption and enhanced renal excretion
HORMONAL CALCIUM CONTROL SYSTEMS
 Maintaining normal blood calcium and phosphorus
concentrations is managed through the concerted action of
three hormones that control fluxes of calcium in and out of blood
and extracellular fluid:
 Parathyroid hormone serves to increase blood concentrations of
calcium.
 Mechanistically, parathyroid hormone preserves blood calcium
by several major effects:
 Stimulates production of the biologically-active form of vitamin D within
the kidney.
 Facilitates mobilization of calcium and phosphate from bone. To prevent
detrimental increases in phosphate, parathyroid hormone also has a
potent effect on the kidney to eliminate phosphate (phosphaturic
effect).
 Maximizes tubular reabsorption of calcium within the kidney. This activity
results in minimal losses of calcium in urine.
Parathyroid hormone is released in response to low
extracellular concentrations of free calcium.
Changes in blood phosphate concentration can be
associated with changes in parathyroid hormone secretion,
but this appears to be an indirect effect and phosphate per se
is not a significant regulator of this hormone.
When calcium concentrations fall below the normal range,
there is a steep increase in secretion of parathyroid hormone.
Low levels of the hormone are secreted even when blood
calcium levels are high. The figure to the right depicts
parathyroid hormone release from cells cultured in vitro in
differing concentrations of calcium.
The parathyroid cell monitors extracellular free calcium
concentration via an integral membrane protein that functions
as a calcium-sensing receptor.
CONTROL OF PARATHYROID HORMONE SECRETION
METABOLIC BONE DISEASES
 Osteoporosis
 Osteodystrophy
 Osteomalacia (rickets in childhood)
OSTEOPOROSIS
 Insufficiency of estrogenes
 Age (both men and women)
 Immobilisation
 Increased levels of glucocorticoids
 Decreased levels of vitamin K2
DISEASE STATES DUE TO HYPERATHYROIDISM- OSTEODYSTROPHIES
 (Both increased and decreased secretion of parathyroid hormone
are recognized as causes of serious disease in man).
 Excessive secretion of parathyroid hormone is seen in two forms:
 Primary hyperparathyroidism is the result of parathyroid gland disease,
most commonly due to a parathyroid tumor (adenoma) which
secretes the hormone without proper regulation. Common
manifestations of this disorder are chronic elevations of blood calcium
concentration (hypercalcemia), kidney stones and remodelation of
bone.
 Secondary hyperparathyroidism is the situation where disease outside
of the parathyroid gland leads to excessive secretion of parathyroid
hormone. A common cause of this disorder is kidney disease - if the
kidneys are unable to reabsorb calcium, blood calcium levels will fall,
stimulating continual secretion of parathyroid hormone to maintain
normal calcium levels in blood. Secondary hyperparathyroidism can
also result from inadequate nutrition - for example, diets that are
deficient in calcium or vitamin D, or which contain excessive
phosphorus (e.g. all meat diets for carnivores). A prominent effect of
secondary hyperparathyroidism is remodelation of bone, leading to
pathologic fractures or "rubber bones".
DISEASE STATES DUE TO HYPOPARATHYROIDISM
 Inadequate production of parathyroid hormone hypoparathyroidism
- typically results in decreased
concentrations of calcium and increased
concentrations of phosphorus in blood.
 Common causes of this disorder include surgical
removal of the parathyroid glands and disease
processes that lead to destruction of parathyroid
glands. The resulting hypocalcemia often leads to
tetany and convulsions, and can be acutely lifethreatening.
Treatment focuses on restoring normal
blood calcium concentrations by calcium infusions,
oral calcium supplements and vitamin D therapy.
Gene families PTH a PTHrP: PTHrP, PTH and TIP39 may be
members of one gene family. Their receptors PTH1R
and PTH2R are 7 transmembrane G protein-coupled
receptors.
VITAMIN D (CALCITRIOL)
 Bioactive vitamin D or calcitriol is a steroid
hormone that has long been known for its
important role in regulating body levels of
calcium and phosphorus, and in mineralization
of bone.
 This hormone has biologic effects which extend
far beyond control of mineral metabolism.
Vitamin D- synthesis
Non-enzymatic reaction in the skin
Transport to liver
UV radiation 270 – 300 nm
Fotolýza
(trvá asi 12 dní)
Liver Kidneys
Inactive form
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
VITAMIN D RECEPTOR BINDING AND
INTERACTIONS WITH DNA
 Being lipids, steroid hormones enter the cell
by simple diffusion across the plasma
membrane. The receptors exist either in the
cytoplasm or nucleus, which is where they
meet the hormone. When hormone binds to
receptor, a characteristic series of events
occurs:
 Receptor activation is the term used to
describe conformational changes in the
receptor induced by binding hormone. The
major consequence of activation is that the
receptor becomes competent to bind
DNA.
Vitamin D at the level of DNA
VITAMIN D RECEPTOR BINDING AND INTERACTIONS WITH DNA
 Activated receptors bind to "hormone
response elements", which are short specific
sequences of DNA which are located in
promoters of hormone-responsive genes. In
most cases, hormone-receptor complexes
bind DNA in pairs, as shown in the figure
below.
 Transcription from those genes to which the
receptor is bound is affected. Most
commonly, receptor binding stimulates tor
inhibits transcription of different genes. The
hormone-receptor complex thus functions
as a transcription factor.
Nuclear receptor function
Regulation of gene expression by VDR
THE VITAMIN D RECEPTOR AND MECHANISM OF ACTION
 The vitamin D receptor forms a complex with
another intracellular receptor, the retinoid-X
receptor, and that heterodimer is what binds
to DNA. In most cases studied, the effect is to
activate transcription, but situations are also
known in which vitamin D suppresses
transcription.
 The vitamin D receptor binds several forms of
cholecalciferol. Its affinity for 1,25dihydroxycholecalciferol
is roughly 1000 times
that for 25-hydroxycholecalciferol, which
explains their relative biological potencies.
VITAMIN D DEFICIENCY
 The classical manifestations of vitamin D deficiency are rickets,
which are seen in children and results in bony deformabilitieas
including bowed long bones.
 Deficiency in adults leads to the osteomalacia. Both rickets and
osteomalacia reflect impaired mineralization of newly
synthesized bone matrix, and usually result from a combination
of inadequate exposure to sunlight and decreased dietary
intake of vitamin D.
 Vitamin D deficiency or insufficiency occurs in several other
situations, which you might predict based on the synthetic
pathway described above:
 Genetic defects in the vitamin D receptor: a number of different
mutations have been identified in humans that lead to
hereditary vitamin D resistance.
 Severe skin, liver or kidney disease: this can interfere with
generation of the biologically active form of vitamin D.
 Insufficient exposure to sunlight: Elderly people that stay inside
and have poor diets often have at least subclinical deficiency.
VITAMIN D DEFICIENCY
 Sunscreens, especially those with SPF
ratings greater than 8, effectively block
synthesis of vitamin D in the skin.
 Vitamin D toxicity: Excessive exposure to
sunlight does not lead to overproduction
of vitamin D. Vitamin D toxicity is
inevitably the result of overdosing on
vitamin D supplements. Ingestion of
milligram quantities of vitamin D over
periods of weeks of months can be
severely toxic to humans and animals.
HERITABILITY OF VITAMIN D INSUFFICIENCY
 2 GWASy – 3 polymorphic areas
 4p12- GC gene(rs2282679)
 11q12- DHCR7/NADSYN1 (rs2211q12)-7dehydrocholesterol
reduktase/NAD
synthetase 1
 11p15-CYP2R1 (rs10741657)-cytochrom P450,
subfamily IIR
 1-4% of the whole variance of serum
25(OH)D3 levels
VITAMIN D AND HEALTH
Deficit and insufficincy of vitamin D = global healthy problem.
High risk for acute and chronic disease, as
 Infection diseases
 Autoimmune diseases
 DM type I and II
 High risk of atherosclerosis
 Some tumor types (colorectal carcinoma, breast and prostate cancer, ovarial
cancer)
 Cognitive dysfunction
 Infertility
 Gravidity and around delivery complications
Pludowski P et al. Vitamin D effects on musculoskeletal health, immunity,
autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia
and mortality—A review of recent evidence, Autoimmunity Reviews, Volume 12,
Issue 10, August 2013, Pages 976-989
INSUFFICIENCY OF VITAMIN D
 Can be recognised in a half of „healthy“ adults
in developped countries.
 Vitamin D levels in the winter seems to be too
low in latitude more than 35° without
supplementation by sunshine and diet
 High heritability - to 53% - important influence
of gene polymorphisms (SUNLIGHT
consortium – Study of Underlying Genetic
Determinants of Vitamin D and Highly Related
Traits, based 2008)
CALCITONIN
 Calcitonin is a hormone known to participate in calcium
and phosphorus metabolism. It main role is to increase
calcium deposition in bones.
 In mammals, the major source of calcitonin is from the
parafollicular or C cells in the thyroid gland, but it is also
synthesized in a wide variety of other tissues, including the
lung and intestinal tract.
 Calcitonin is a 32 amino acid peptide cleaved from a
larger prohormone. It contains a single disulfide bond,
which causes the amino terminus to assume the shape of
a ring.
 Alternative splicing of the calcitonin pre-mRNA can yield
a mRNA encoding calcitonin gene-related peptide; that
peptide appears to function in the nervous and vascular
systems. The calcitonin receptor has been cloned and
shown to be a member of the seven-transmembrane, G
protein-coupled receptor family.
CONTROL OF CALCITONIN SECRETION
 The most prominent factor controlling
calcitonin secretion is the extracellular
concentration of ionized calcium.
 Elevated blood calcium levels strongly
stimulate calcitonin secretion, and secretion is
suppressed when calcium concentration falls
below normal.
 A number of other hormones have been
shown to stimulate calcitonin release in certain
situations, and nervous controls also have been
demonstrated.
Vitamin K1
Vitamin K2
Vitamin K
 Vitamin K1 (fylochinon) – plants origin.
 Vitamin K2 (menachinon) – produced by
intestinal microbiota
 K1 and K2 are used by different manner
+ K1 – especially for blood clotting (liver)
 K2 – important in non- coagulation
processes : cell growth and vessel wall
cells metabolism.
 Vitamin K2 is transcriptional regulator of
genes specific for bone. It is functioning
using SXR (steroid and xenobiotic
receptor) and supports expression of
osteoblastic markers. It supports bone
homeostasis.
Syntetické deriváty Vit.K
Vitamin K - function
 Cofactor of liver microsomal carboxylase → changes
glutamates on γ-carboxyglutamates during
posttranslational modification of coagulation factors II,
VII, IX and X.
 This modification enables to bind vitamin K-dependent
coagulation factors through Ca2+ ions to phospolipids
of platelets.
 It forms similar binding of Ca2+ and other proteins –
osteocalcin in bone.
o Vitamin K2 is able to catalyze conversion of specific residua of
glutamic acid to Gla residuals.
o Vitamin K2 is necessary for γ-carboxylation of bone matrix proteins
containing Gla, as is MGP (= matrix Gla protein) and osteocalcin.
o Incomplete γ-carboxylation of osteocalcin and MGP leads to
osteoporosis and an increased risk of pathological fractures. Vitamin
K2 stimulates synthesis of osteoblastic markers and the bone
deposition.
o Vitamin K2 decreases bone resorption by osteoclast formation
inhibition and by decreasing of their resorption activity.
o Vitamin K2 treatment induces apoptosis of osteoclasts, but inhibits
apoptosis of osteoblasts which leads to increased formation of bone
mass.
o Vitamin K2 supports osteocalcin expression ( mRNA) which can be
further modulated by 1,25-(OH)2 vitamin D3.
Vitamin K and bones
SXR and its effects
Inoue KH a Inoue S: J Bone Miner Meat (2008) 26: 9-12
DĚKUJI ZA POZORNOST