Cell Signaling Pathways: Steroid Hormones, Vitamin D3 Flashcards
is vitamin D a hormone or a vitamin?
both, it is converted to a hormone and it is a vitamin throughout diet
sources of vitamin D (2)
the sun
diet
sun as a source of vitamin D
bare skin exposure 5-10 minutes, 2-3 times per week (depends upon time of year and latitude)
how does vitamin D affect your teeth?
vitamin D helps reduce the risk of cavities by producing cathelicidin and denfensins
cathelicidin and denfensins have — effects to fight bacteria that cause cavities
antibacterial
research shows that vitamin D deficiency can contribute to
cavities
studies show children with severe early childhood cavities had much lower
vitamin D levels than children without severe childhood cavities
biologically active form of vitamin D3
1a,25 (OH2)D3
circulating form of vitamin D3 hormone
25 (OH2)D3
what provides the major of the circulating 1,25 (OH2)D3?
the kidney
what else can synthesize 1,25 (OH2)D3 for use in an autocrine or paracrine mechanism? (2)
skin and a variety of immune cells
what are serum levels of 25 (OH2)D3 an indicator of?
how much Vitamin D is entering the host
how is 25 (OH2)D3 transported through the serum?
vitamin D binding protein (DBP) (or transcalciferin, TC)
transcalciferin
a membrane of the albumin family of proteins
ergocalciferol
plant/fungi form and most commonly found in dietary supplements and many fortified foods
ergocalciferol vs cholecalciferol
less absorbable, less potent and shorter acting than cholecalciferol
what do the best vitamin supplements contain?
cholecalciferol
both ergocalciferol and cholecalciferol undergo a conversion to (2)
25 (OH2)D3 and 1a25 (OH2)D3
what is the active form of 1,25 (OH2)D3 known as?
calcitriol (vitamin D3)
how does 1a,25 (OH2)D3 exert its cellular actions?
by binding to the vitamin D receptor in target cells
the vitamin D receptor mediates the nuclear actions of
1a,25 (OH2)D3
the affinity of the receptor varies dramatically with —- having the highest affinity by several log orders
1a,25 (OH2)D3
vitamin D receptor (VDR)
a transcription factor regulating the expression of genes which mediate its biological activity (member of large family of nuclear hormone receptors)
VDR is widely distributed among —, not just classic targets of vitamin D
tissues
upon binding 1a,25 (OH2)D3, VDR forms a heterodimeric complex with other nuclear hormone receptors, particularly the
retinoid-x-receptor (RXR)
heterodimeric complex binds to DNA promoter sequences containing the — sequences in genes it regulates
VDRE (vitamin D response element)
what complexes with activated VDR/RXR heterodimers to recruit the proteins required for transcription such as RNA polymerase 2 to the transcription start site?
co activators
expression of the TRPV6 calcium channel gene is
vitamin D3 dependent
genes which positively regulate intestinal trans cellular ca2+ transport (3)
TRPV6
calbindins
CaATPase
genes expressed by oestobalsts which are needed to form bone (2)
collagen
alkaline phosphatase
1,25 (OH2)D3 also induces expression of RANKL, which is required for
osteoclast formation
anti-microbial peptides produced by salivary glad and mucosal epithelium (2)
defenses
cathelicidins
the defenses and cathelicidins have broad antimicrobial activity against gram-negative and gram-positive bacteria and are effective against oral microorganisms such as (3)
streptococcus mutants
porphyromonas gingivalis
actinobacillus actinomycetemcomitans
streptococcus mutants is the active agent which causes
caries
porphyromonas gingivalis has been commonly implicated in
periodontal disease
what is the major role of vitamin D3?
control of Ca2+ homeostasis in the circulation
severe vitamin D3 deficiency is best known to cause —, but over 200 diseases have been linked to vitamin D3
rickets
adequate levels of vitamin D3 are needed for development of (2)
strong bones and teeth
vitamin D3 is now appreciated to play significant roles in muscle and immune function as well as in the prevention of (5)
colon, breast, prostate cancer diabetes heart disease high blood pressure multiple sclerosis
Vitamin D levels
deficient:
insufficient:
normal:
deficient: <20 ng/ml
insufficient: 20-29 ng/ml
normal: >30 ng/ml
estimates of vitamin D insufficiency/deficiency in the US have been as high as –% have been reported, but small improvements have been observed as awareness grow s
85%
what type of deficiency is linked to nutritional rickets? (2)
calcium
vitamin D
what are the main sources of vitamin D in foods?
fish oils and fortification
most countries… (2)
do not fortify their foods and have low exposure to sunlight
breast-fed infants who do not receive vitamin D supplementation (rare) as breast milk are low in
vitamin D
vitamin D deficiency symptoms include: (5)
prominence of the costochondral junction (rachitic rosary)
deformities of ht back and bowing of the legs
softened calvarium
parietal flattening
frontal bossing and delayed eruption of the permanent dentition and enamel defects
type 1 vitamin D dependent rickets
often manifests by age 2 and in many cases during the first 6 months of life
primary defect is in the 25 (OH2)D1 hydrolase
low circulating 1,25 (OH2)D3
type 1 rickets is treated with
massive doses of vitamin D or 25 (OH2)D3 or lower doses of 1,25 (OH2)D3
type 2 vitamin D dependent rickets
normal at birth, bone disease usually before age 2
normal or high circulating levels of 1,25 (OH2)D3
common to observe alopecia, multiple milia, epidermal cysts and oligodontia
type 1 rickets is treated with
high dose of 1,25 (OH2)D3 and up to 3 gm calcium per day
type 2 is due to a defect in the
receptor, not binding to the receptor
signs of rickets (5)
soft spot on baby head is slow to close bony necklace curved bones big, lumpy joints bowed legs (knees bent out)
osteomalacia
the softening of the bones due to inadequate levels of calcium and phosphate, which are most commonly due to vitamin D deficiency
orange stain:
blue stain:
orange stain: unmineralized osteoid
blue stain: mineralized osteoid
oral manifestations of rickets (5)
developmental abnormalities of dentin and enamel delayed eruption misalignment of teeth in the haw high caries index enamel hypoplasia
There are a number of U.S. studies reporting on the relationship of solar ultraviolet-B (UVB) light and dental caries. These studies stretch over a long period of time:
•During the Civil War,
men living in the Northeast were rejected from the draft at a higher rate than men living to the south. The Northeast has less sunshine than other areas. Men with fewer than 6 opposing teeth were generally not enlisted.
There are a number of U.S. studies reporting on the relationship of solar ultraviolet-B (UVB) light and dental caries. These studies stretch over a long period of time:
In the 1930s,
the number of dental caries among adolescent males was plotted on a map. Dental caries rates were lowest in the Southwest and highest in the Northeast and Northwest. UVB light triggers vitamin D, which increases calcium absorption from food and helps generate proteins that fight bacteria that cause caries.
There are a number of U.S. studies reporting on the relationship of solar ultraviolet-B (UVB) light and dental caries. These studies stretch over a long period of time:
In the mid-1900s,
men enlisting in the armed forces from Texas and nearby states had the fewest caries. The highest number of caries were noted in men living in the Northeast and Northwest. Dental caries rates in the northern Rocky Mountain states were somewhat lower than dental caries rates in states to the east or west. This was probably due to higher surface elevation and more UVB.
There are a number of U.S. studies reporting on the relationship of solar ultraviolet-B (UVB) light and dental caries. These studies stretch over a long period of time:In the 1950s,
schoolchildren living in the sunnier inland counties of Oregon had fewer caries than those living in counties with more fog (mostly coastal regions). These studies ruled out other risk factors for caries such as eating foods with sugar or having fluoride in the water.
which positions within the receptor are those for which mutational changes are found to be detrimental to function?
conserved amino acids positions
what do mutations which affect the DBD and LBD cause?
HVDRR, hereditary vitamin D3 resistant rickets
all patients with mutations in the DBD had HVDRR with alopecia indicating that DNA interaction is also a critical function of the VDR in regulating
hair growth
HVDRR patients with mutations in the LBD that affect ligand binding or co-activator binding do not have
alopecia
psoriasis
immune mediated disease affecting the skin
cure to psoriasis?
none, but vitamin D3 treatment can help to control symptoms
migratory stomatitis in the oral cavity mucosa and tongue are believed to be oral manifestations of
psoriasis
affecting 1-2.5% of the general population
3 ways to manage psoriasis
topical agents
phototherapy
biologicals used systemically
topical agents
Ointments and creams containing coal tar, corticosteroids, vitamin D3, and retinoids are routinely used. Activated vitamin D3 and its analogues can inhibit skin proliferation thus reducing plaque formation.
phototherapy
sunlight (311-313 nm wavelength) effective.
biologics used systematically
Currently Enbrel (etanercept) and Remicade are commonly used. They are TNF-α inhibitors, which reduce inflammation. Stelara is also used and it targets IL-12 and IL-23 to reduce inflammation.
what structures play critical roles in the maintenance of serum ca2_ levels? (3)
skeleton
gut
kidney
ca2+ levels in the serum are sensed by the — gland through
parathyroid gland
calcium sensing receptor (caSR)
ca2+ and phosphate levels are glutted largely by the opposing actions of
PTH and calcitonin (CT)
PTH is produced by
chief cells of the parathyroid
calcitonin is produced in the
parafollicular cells of the thyroid
PTH acts to
increase ca2+ levels
calcitonin acts to
decrease ca2+ levels
PTH results in an increase in
phosphate excretion through the urine,
PTH enhances uptake of phosphate from the (2)
intestine and skeleton into the circulation
These opposing action result in an overall small net decrease in
serum phosphate (Important to note that intestinal uptake of Ca2+ and phosphate is largely mediated by the increase in active Vitamin D3)
key serum ion levels
ionized calcium:
4.5-5.2 mg/dl
key serum ion levels
serum total calcium:
8.8-10 mg/dl
key serum ion levels
phosphate:
2.5-4.5 mg/dl
key serum ion levels
magnesium:
1.7-2.6 mg/dl
what are the physiologically active compartment of serum calcium levels?
free (ionized)
oral tingling sensation in and around the mouth and lips and in extremities is an early symptom of
serum calcium levels
changes of what percentage in calcium are physiologically significant?
10%
causes of hypophosphatemia: (2)
inadequate intake (alcoholics) increased excretion (hyperparathyroidism, hypophosphatemic rickets)
normally, very difficult to attain hypophosphatemic status due to diet since phosphorus is extremely abundant in our environment and in our food. generally we only see hypophosphatemia in situations of
malnutrition
PTH # of amino acids
84
pre-pro-PTH
large PTH precursor of 115 aa
what is the chief function of PTH?
to maintain the concentration of ionized calcium in the extracellular fluid
what are the two PTH receptors in evolved in ca2+ homeostasis?
PTH1R
PTH2R
PTHrP
produced by various cells (plays an important role in tooth eruption and endochondral bone formation) and by some tumors
closely related homolog of PTH
what does PTH1R bind to? (1)
both PTH and PTHrP
referred to as the type 1 PTH/PTHrP receptor
PTHrP does not stimulate production of — from the kidney
1.25(OH)2D3
FORTEO (teriparatide)
biologically active PTH(1-34) is FDA approved drug
FORTEO (teriparatide) is used for treatment of
postmemopasual osteoporosis (2 yr max usage)
how is the calcium-sensing receptor (CaSR) activated?
extracellular Ca2+and di-, tri- or polyvalent cations, polyamines, and aromatic and other L-amino acids
what does CaSR regulate the release of?
PTH
in the kidney, CaSR located on several different regions, where it plays a role in the control of reabsorption of (4)
several different regions, where it plays a role in the control of reabsorption of ca, phosphate, na, and water
the CaSR is encoded by the — gene and is a
CASR
G protein coupled receptor
covid 19 and vitamin D
recently there have been reports that individuals who have adequate levels of vitamin D do better than n individuals who are vitamin nD deficient when exposed to covid 19
–One study found that people with low levels had a slightly higher chance of testing positive–Another study found that high levels of Vitamin D lower your risk of severe infection, especially among Black individuals.–Another study found no evidence that higher levels of Vitamin D lowered risk of infection, hospitalization or severity of disease.
