wk 12, lec 1 Flashcards
2 forms of vitamin D and where re they obtained from
- Vitamin D2 (ergocalciferol)
- Vitamin D3 (cholecalciferol)
D2=diet
D3=skin via sun
vitamin D synthesis
UVB exposure causes 7-dehydrocholesterol in skin to be converted into provitamin D3 –> D3 cholecalciferol
transport to liver: via blood and undergo hydroxylation by enzyme 25- hydoxylase to become 25-hydroxyvitamin D (calcidiol or 25(OH)D)
transport to kidneys: 25-hydroxyvitamin D undergoes another hydroxylation via 1-alpha-hydroxylase; add hydroxyl group in proximal tubule ONLY WHEN stimulated by PTH –> form calcitiriol (1,25-
dihydroxyvitamin D or 1,25(OH)2D) which is biologically active
steps of vitamin D synthesis from UVB
in skin: D3 cholecalciferol
then 2 hydroxylations
in liver: form 25-hydroxyvitamin D (calcidiol or 25(OH)D)
[[via 25-hydroxylase]]
in kidney: form Calcitriol (1,25-
dihydroxyvitamin D or 1,25(OH)2D),
[[via 1-alpha-hydroxylase]]
calcitriol (active form of vitamin D3) synthesis is regulated by? and what do they influence?
- Parathyroid hormone (PTH)
- Serum calcium levels
- Fibroblast growth factor 23 (FGF23)
Influence the activity of 1-alpha-hydroxylase.
impact of high and low serum calcium on calcitriol production
i.e. low Ca2+ stimulates PTH which stimulates 1-alpha-hydroxylase to increase calctriol production
high Ca2+ and high FGF23 inhibit 1-alpha-hydrpxylase to reduce calcitriol production
calcitriol functons
-intestinal absorption of calcium and phosphorus (via cal binding-D protein expression)
-bone health (mineralization by stimulating phosphorus and calcium deposition)
-renal reabsorption (regulate Ca2+ and P)
-PTH regulation
low Ca2+ ____ to PTH
increases PTH secretion –> increase vitamin D
causing a mobilization of calcium from bone and intestines
negative feedback loop
calcium and location
majority in bone; a bit in GI/blood
lost in feces from diet; gastric juices
calcium in bone formation
calcium phosphate crystals;
hydroxyapatite crystals
osteoblasts secrete osteocalcin and osteopontin to bind to calcium ions
osteocalcin and osteopontin act as nucleation sites for calcium phophate crystals
Ca2+ and phosphate ions combine to form crystals –> deposit into collagen in bone matrix
osteoblasts secrete ___ and. ____ to bind to calcium ions
osteocalcin and osteopontin
3 hormones that regulate calcium levels in body
- Parathyroid Hormone (PTH)
- Calcitonin
- Calcitriol
how PTH affects calcium
low serum Ca2+ –> production of PTH –> stimulates osteoclasts –> bone resorption and release Ca2+ into blood
enhance renal reabsorption of ca2+ in kidney (less urinary excretion)
stimulate calcitiriol (vitamin D) production in kidney (promote intestinal absorption of calcium)
calcitonin and PTH relationship
OPPOSITE
calcitonin via high Ca2+
PTH via low serum Ca2+
calcitonin impact on calcium
high Ca2+ –> calcitonin secretion from thyroid
inhibit osteoblasts; promote bone deposition of ca2+
suppress renal tubular reabsorption of calcium, increase urinary excretion
vitamin D (calcitriol) impact on calcium
increase intestine absorption (protein express for active transport)
promote bone mineralization and increase ca2+ deposition
regulate renal reabsoprtion of ca2+ and phosphorus
actions of PTH, calcitriol and calcitonin impacting calcium
- PTH increases plasma Ca2+ by mobilizing this ion from bone
- It increases Ca2+ reabsorption in the kidney, but this may be offset by
the increase in filtered Ca2+ - It also increases the formation of 1,25-dihydroxycholecalciferol
(Calcitriol) - Calcitriol increases Ca2+ absorption from the intestine and increases
Ca2+ reabsorption in the kidneys - Calcitonin inhibits bone resorption and increases the amount of Ca2+ in
the urine.
phosphorus roles in the bone
mineralization of bone matrix (hydroxyapatite crystals)
phosphate needed for synthesis of osteoblast proteins like osteocalcin and osteopontin
high phosphate inhibits osteoclasts, low phosphate stimulates osteoclasts
acts as buffer to maintain pH in bone
regulate gene expression in bone
PTH and calcitriol for phosphorus metabolism
PTH impact on phosphorus
PTH increases blood phosphorus levels by promoting its release from
bone tissue and enhancing its reabsorption in the kidneys
2 forms of vitamin K and where they are found
- Vitamin K1 (phylloquinone)
- found in green leafy vegetables
- Vitamin K2 (menaquinone)
- synthesized by bacteria in the gut and found in fermented foods
and animal products
vitamin K synthesis b ia gut bacteria
bacteria convert dietary precursors, such as phylloquinone
(vitamin K1) and menadione (a synthetic form of vitamin K), into
menaquinones (vitamin K2)
absorption of vitamin K1
then transport and conversion
in the small intestine, along with dietary
fats, through a process that requires bile salts and pancreatic enzymes
transport via lymph into blood into liver and then get converted into active form
vitamin K impact on bone metabolism
carboxylation of osteocalcin (protein made by osteoblasts) ; turns it into active from where it binds ca2+ ions and promotes deposition into bone
bone mineral density
osteoblast function
how does PTH regulate calcium in blood?
It does this through:
* Calcium mobilization from bone
* Absorption from the intestines
* Reabsorption in the kidneys
- PTH stimulates osteoclast activity, leading to bone resorption and subsequent release of calcium into the bloodstream
PTH impact on bone
increase bone resorption; mobilize ca2+
increase phosphate excretion in urine
–> phosphaturic action via NaPi-IIa in proximal tubules
-increase ca2_ reasbortption in distal tubules
PTH also increases the formation of 1,25-dihydroxycholecalciferol, and this
increases Ca2+ absorption from the intestine
how PTH mobilizes. calcium from ER
cAMP –> Gs and adenylyl cyclase –> DAG and IP3 –> PLC –> PKC…
regulation of secretion of PTH via calcium and feedback?
circulating Ca2+ negative feedback onto parathyroid gland via Ca2+ sensing receptor CaSR –> activate GPCR to inhibit PTH secretion
- When the plasma Ca2+ level is high, PTH secretion is inhibited and
Ca2+ is deposited in the bones - When it is low, secretion is increased and Ca2+ is mobilized from the
bones
PTH inhibition of osteoblasts
- Indirect Inhibition via RANKL
- Stimulation of RANKL Expression
- Inhibition of osteoblast differentiation
- Alteration of WNT Signalling
PTH impacting RANKL
indirectly inhibit osteoblasts via RANKL and OPG system
increase RANKL by osteoblasts –> osteroclastogenesis (osteoclast) and bone resorption
osteoblast RANKL vs OPG impacts
RANKL= activate osteoclasts
OPG= decoy receptor binding RANKL and inhibit osteoclasts
PTH inhibits osteoblast differentation
stop osteoblast precursors from becoming mature via impacting transcription factors Runx2 and Osterix for osteoblast differentation
PTH alters Wnt signalling
Wnt for osteoblast differentation and function
PTH suppresses Wnt signaling and inhibits bone formation
hypoparathyroidism impacts on bone health
decrease bone resorption (reduced osteoclast activity) –> less ca2+ and phosphate from bone into bloodstream
decreased bone turnover/impaired bone remodelling since less osteoclast activity
increase bone mineral density (more prone to fracture)
clinical manifestations of hypoparathyroidism
Muscle cramps
* Tetany
* Paresthesias
* Seizures.
* Increased serum phosphate levels (hyperphosphatemia) due to decreased renal phosphate
excretion.
* increase bone mineral density but prone to fracture
* hypocalcemia (tingling, tetany)- neuromscular irritability
sings of hypocalcemia seen in hypoparathyroidism
Trousseau sign (a contraction of forearm muscles when the blood pressure cuff is placed
around the arm and inflated to above systolic pressure), and Chvostek sign (twitching of
facial muscles when the facial nerve is tapped). Patients also have cardiac arrhythmias.
hyperparathyrdoidims impacts on bone
increase bone resorption and osteoclast activity –> more ca2+ and phospahte from bone into blood
accelerate bone turnover and net loss of bone mass –> osteopenia or osteoporosis
bone pain
clinical manifestations of hyperparathrydoisim
- Fatigue
- Hypophosphatemia (low blood phosphate levels) due to increased renal phosphate excretion.
- hypercalcermia
- Fractures due to weakened bones
- Skeletal manifestations include osteopenia, osteoporosis, bone pain, and an increased
risk of fractures - Kidney stones
- Psychiatric symptoms; abdominal pain.
- Seizures
- Constipation, muscular weakness, and hypotonia:
–> * High calcium levels hyperpolarize the neuromuscular membranes; therefore, muscle
is refractory to stimulus, resulting in weakness and constipation. - Electrocardiogram has short QT interval
hypo vs hyperparathyroid and impacts on ca2+ and phospahte
hypo: in blood low ca2+ (less osteoclasts), high phosphate (less renal excretion)
hyper: in blood high ca2+ (more osteoclasts) and low phosphate (increased renal excretion)
boron influence on calcium metabolism
Enhances the absorption of calcium by stimulating the conversion of vitamin D
to its active form, calcitriol thus promotes calcium uptake in the intestines
boron impacting collagen synthesis
enhance enzyme activity = more collagen
boron impacting mineralization of bone
more deposition of Ca2+ and Mg2+ into bone matrix
boron impacting homrone regulation
estrogen and testosterone –> influence bone turnover and remodeling
boron impact on inflammation
reduce
maintain bone health by mitigating inflammatory processes that could
otherwise lead to bone degradation
boron impact on vitamin D metabolism
- May enhance the conversion of vitamin D to its active form
- Promoting calcium uptake and utilization in bone tissue
silicon impacts on collagen fromation
Silicon may enhance the cross-linking of collagen fibers, thereby improving the structural
integrity of bone.
silicon and matrix mineralization in bone
Facilitates the deposition of minerals such as calcium, phosphorus, and magnesium onto the collagen framework
silicon and osteoblasts
increase activity
silicon and bone resorption
inhibits osteoclasts; stops bone resorption
silicon and collegenase
inhibit activity of collagen-degrading enzymes known as collagenases
silicon and gene expression
regulate the expression of genes related to collagen synthesis, osteoblast
differentiation, and mineralization processes
* Exerting a positive effect on bone health
magnesium impact on mineralization
deposit hydroxyapatite crystal (add to calcium phosphate complexes)
magneisum impact on osteoblasts
stimulate them and promote bone formation
magnesium impact on osteoclast function
May modulate the production and activity of factors involved in osteoclast regulation, such as
RANKL (Receptor Activator of Nuclear Factor κB Ligand) and OPG (Osteoprotegerin)
magnesium impact on calcium homeostasis
- Regulates the activity of various calcium channels, pumps, and transporters
involved in calcium absorption, distribution, and excretion - Also modulates the secretion of parathyroid hormone (PTH)
magensium impact on vitamin D metabolism
required for the conversion of vitamin D into its active form, calcitriol, in the
kidneys
magnesium impact on inflammation
anti inflammatory
Chronic inflammation can contribute to bone loss and osteoporosis, and
magnesium supplementation may help mitigate inflammation-related bone damage
growth hormone impact on chrondrocytes
impacts growth plates (epiphyseal plates)
chondrocytes in growth plates proliferate and hypertrophy –> longitudinal bone growth
growth hormone impact on IGF-1 (insulin like growth factor)
stimulate IGF1 which stimulates bone growth and chondrocytes and osteoblasts
growth homrone impact proteins
synthesis i.e. collagen
growth hormone impact on osteoblasts and osteoclasts
osteoblasts: stimulates
osteoclasts:inhibits
growth homrone impacts on calcium and phosphate metabolism
Promotes the intestinal absorption of calcium and phosphate, as well as the renal retention
of these minerals, ensuring an adequate supply for bone mineralization and growth.
estrogen impact on osteoblasts
increase osteoblasts –> collagen and bone matrix
inhibits apoptosis of osteoblasts
estrogen impacts on osteoclasts
Suppresses the differentiation of osteoclast precursor cells into mature osteoclasts
induce osteoclast apoptosis
- Affects the activity of mature osteoclasts by modulating the expression of genes
involved in bone resorption - It inhibits the production and secretion of enzymes, such as tartrate-resistant acid
phosphatase (TRAP) and cathepsin K, which are essential for osteoclast-mediated
bone resorption
what does estrogen secrete to inhibit osteoclasts
- It inhibits the production and secretion of enzymes, such as tartrate-resistant acid
phosphatase (TRAP) and cathepsin K, which are essential for osteoclast-mediated
bone resorption
