Calcium
Calcium enters the cell, either directly from the blood by channels:
A voltage-dependent slow channel A ligand-gated channel channel A stretch-activated channel
Urinary calcium excretion is decreased......
With PTH secretion. In the presence of phosphorus, potassium, magnesium and boron.
Calcium decreases the absorption of ______________ _________, favorable influencing the lipid profile (↓TC & LDL & ↑ HDL) and FA profile of bile (↓colon CA).
fatty acids
The ground substance of bone is comprised of ______________ and _____________.
glycoproteins and proteoglycans
Large intakes of calcium may result in ______________ (calcium intakes > 3g/d), deposition of calcium in the soft tissues as well as constipation, bloating, gas and low back pain
hypercalcemia
Bones and teeth contain about 99% of the calcium in the body. The other 1% is distributed in the ____________ and _______ fluids.
intracellular- and extracellular fluids.
Only ________ calcium is absorbed.
ionized
Serum ______________ calcium (free) can reflect alterations in calcium metabolism
ionized
In either case, the role of __________ ____________ (carrier of 2 positive charges) in the intrinsic or extrinsic pathway is to associate with the negative charges on the vitamim K-dependent gamma-carboxyglutamate (Gla) residues (negative charges) of the different clotting factors (Factors II, VII, IX and X), allowing the binding of the blood clotting proteins to membranes (polar heads).
ionized calcium
Some osteoblasts differentiate into a fourth type of bone cell is called ________ ________. These flat cells form a membrane called the periosteum which covers the bone and separates the bone from bone fluid. This membrane covering also contains calcium pumps. o The _______ __________ regulate the flux of minerals in/out of bone.
lining cells
Diets high in ___________ but low in _________ may result in mild hyperparathyroidism and a loss of calcium. Calcium loss from the bone Calcium loss through GI secretions
phosphorus, calcium
Dietary ________ promotes urinary losses of calcium.
protein
Within an organelle, calcium is bound to __________ such as calsequestrin in the sarcoplasmic reticulum or complexed to phosphate in the mitochondria.
protein
The release of calcium from these intracellular sites requires the use of a _________ such as the calcium-sodium antiport or a release channel.
pump
About _______ - _______% of the weight of bone is due to minerals such as calcium, phosphorus, fluoride, magnesium, potassium, sodium, strontium as well as carbonate and hydroxyl groups.
60-66%
Normal blood calcium concentrations: _________ - ________mg/dL
8.5-10.5 mg/dL
Normal serum calcium concentrations range fro ________ to _________ mg/dl for adults
8.5-10.5 mg/dl
Operates primarily in the duodenum and proximal jejunum. Is saturable at low to moderate calcium intakes. Requires energy (ATP). Regulated by the active form of vitamin D (calcitriol). Accounts for >60% of calcium absorption in the small intestine at calcium intakes of 400-500 mg/meal.
A Saturable, Carrier-Mediated, Active Transport System
Once the membrane _____________ (the nerve impulse is turned off, acetylcholine is not released and sodium does not cross the membrane of the motor nerve), calcium is returned via a pump system to it intracellular storage site in the muscle cell (sarcoplasmic reticulum). Troponin loses its calcium so the actin and myosin filaments stop interacting with each other and the muscle returns to resting conditions.....the muscle contraction stops
repolarizes
Too much calcium will cause muscle ______. Too little calcium will cause ________ or _____________ ____________ __________.
rigor, tetany or spasmodic muscle contraction.
Concentrations of calcium in the cytoplasma can also be increased by __________ __________that stimulate the release of calcium from intracellular sites such as the ER, sarcoplasmic reticulum and mitochondria
second messengers
Excessive intakes of calcium (especially calcium carbonate) may also cause constipation, particularly in women who have a ___________ GI tract than men
slower
The binding of acetylcholine to its receptor causes a change in the membrane, allowing an influx of ___________ions (membrane depolarization). This action potential moves along the muscle fiber.
sodium ions
The ___________ from high BV sources of protein may cause a decrease in calcium absorption in the GI tract and well as an increased loss of calcium in the urine.
sulfur
The factors used in the process of blood clotting such as ___________ (circulates in its inactive or zymogen form, prothrombin) and factors _____ and _____ circulate in the blood or in the tissue (factor VII) until they are activated either by the Intrinsic Pathway or Extrinsic Pathway, respectively.
thrombin, factors XII and XI
Vitamin D stimulates the synthesis of a calciumbinding transport protein called calbindin D9k (CBP). o Calbindin D9K shuttles calcium across the cytosol of the enterocyte
Intracellular transport of calcium through the intestinal cell:
This non-saturable, paracellular passive diffusion system occurs throughout the small intestine, but primarily works in the jejunum and ileum when concentrations of calcium are high. Absorption of calcium occurs between cells rather than through the cell
Passive paracellular absorption:
This system is not regulated. It requires no carriers or energy. Increase concentrations of intracellular calcium ions may"open" the junctions between cells through a series of reactions to enhance calcium absorption by this system. Vitamin D also enhances the expression of genes that code for specific membrane proteins (claudins) that are necessary for calcium absorption by this system in the gut
Passive paracellular absorption:
Demineralization of mainly trabecular bone Occurs mostly in PM women (50-65YOA)...about 10- 15yrs after menopause. o Can occur in younger women (and men) with an eating disorder Related to decrease in estrogen production o Stimulates osteoblast activtiy o Decreases osteoclast activity o Stimulates vitamin D formation
Type I /Primary/Postmenopausal Osteoporosis
With the transmission of a nerve impulse to the end of a motor neuron, calcium is allowed to enter the nerve ending which causes the release of ____________. The released ___________________, in turn, binds to its receptor on the muscle cells.
acetylcholine.
Calcium salts in foods and supplements must be exposed to an ________ _________ such as the HCL of the stomach for ~ 1 hour, in order, to release (solubilize) the calcium from its salt.
acidic pH
Ionized calcium is "____________" calcium.
active
Calcium may form complexes with other minerals and dietary substances in the small intestine due to the _________ _______
alkaline pH
Increased production of vitamin D stimulates the synthesis of the vitamin D-dependent protein called ________ __________ which increases the intestinal absorption of calcium
calbindin D9k
The inner layer of bone that is surrounded by cortical bone. has as a spongy appearance. is more metabolically active than cortical bone. consists of a system of mineralized proteins (Type 1 collagen). is found mainly in the vertebral and pelvic regions....which accounts for the clinical endpoints of osteoporosis: hip & vertebral fractures!
Trabecular Bone
Vitamin D stimulates changes in the membrane lipid composition and topology, favoring calcium absorption via an epithelial calcium channel called TRPV6 (transient receptor potential vanilloid 6).
Transport of calcium across the brush border membrane:
What are the three steps in A Saturable, Carrier-Mediated, Active Transport System.....
Transport of calcium across the brush border membrane: Intracellular transport of calcium through the intestinal cell: Extrusion of calcium across the basolateral membrane:
The nerve impulse triggers the release of calcium from the sarcoplasmic reticulum. This increase in calcium inside the muscle cell allows calcium to bind to __________ ____. The binding of calcium to _________ ____, in turn, allows the interaction between the actin and myosin filaments which results in muscle contraction.
Troponin C
RDA: Adult men, age 19-70 yr and adult women (including pregnant and lactating women), age 19-50 yr: _________ mg/d
1,000
RDA: Adult women > 51YOA and adult men > 71 YOA: __________ mg/d
1,200 mg/d
Major minerals are required by the body in amounts > ____ mg/d. A
100 mg/d. A
Calcium absorption from the diet ranges from _____ - _____% while the absorption of calcium from dairy products ranges from _____ - ______%. During periods of growth, calcium absorption can be as high as ____%.
20-50%, 20-35%, 75%.
Normal serum ionized calcium levels range from _________ to ___________ mg/dL for adults
4.5-5.6 mg/dL
This system requires three sequential steps. Each step is regulated by vitamin D. Thus, any condition that adversely affects vitamin D formation such as the effects of aging on renal function; the effects of aging on the expression of TRPV6 and calbindin; the presence of renal or liver disease; the presence of elevated concentrations of blood phosphorus or the presence of estrogen deficiency will adversely affect the calcitriol-dependent system of calcium absorption.
A Saturable, Carrier-Mediated, Active Transport System
Calcium is absorbed throughout the small intestine by two main transport processes:
A Saturable, Carrier-Mediated, Active Transport System Passive paracellular absorption:
_________ levels will affect serum calcium levels. o For each 1 g/dl decrease in serum __________, serum calcium will decrease 0.8 mg/dl. o Measure ____________ levels along with total calcium
Albumin
____________ in the large intestine may cause the release of calcium bound to some fermentable fibers such as pectins and gums in the large bowel, making calcium available for absorption.
Bacteria
Functions and mechanisms of calcium:
Bone Mineralization Blood Clotting Nerve Conduction Muscle Contraction Membrane Permeability Enzyme Regulation
________ supplements (3 mg/d) when ingested with ___________ (200 mg/d) can increase urinary losses of calcium
Boron, magnesium
_____________ (300-400 mg/d) can increase the urinary excretion of calcium (10 mg/d) by decreasing re-absorption of calcium in the kidney
Caffeine
_______________ can also increase fecal losses of endogenous calcium by increasing the amount of calcium secreted in the gut.
Caffeine
Calcium absorption requires ________, ___________ and _____________!
Calcium, vitamin D and magnesium!
As discussed in the vitamin K section of Chapter 10, calcium ions along with vitamin K are required for blood to _________ or, in more technical terms, for fibrinogen (a soluble protein) to be converted into fibrin (an insoluble protein). Furthermore, for blood to _______ and bleeding to stop, many fibrin molecules bind together to form large polymers which eventually form a mesh through cross-linking.
Clot
Remember from the chapter on fiber in DIET451, calcium adsorbed to fermentable fibers (pectins, gums and some hemicelluloses) in the upper GI may be released and absorbed in the lower bowel as the fiber is fermented by __________ bacteria
Colonic
The outer compact layer of bone that is composed of layers of mineralized protein (type 1 collagen).
Cortical Bone
_______________ intakes of calcium (>4mg/kg of BW/d) may increase the risk of developing calcium-containing kidney stones in those with idiopathic hypercalciuria.
Excessive
This pathway is activated at the site of injury with the exposure of Tissue Factor. This "tissue factor", along with other blood clotting proteins and calcium, causes the activation or factor VII, forming factor VIIa. Then, factor VIIa along with its cofactor (tissue factor) and calcium stimulate the formation of factor Xa from factor X.
Extrinsic Pathway:
Calcium is pumped from the intestinal cell into the extracellular fluid via a Ca2+ -Mg2+ ATPase or pump. Sodium may also be used. The pump is stimulated by vitamin D
Extrusion of calcium across the basolateral membrane:
These pathways (the intrinsic and extrinsic pathways) are not independent of each other. Both pathways result in the activation of _________ _______ (i.e factor Xa) which catalyzes the conversion of prothrombin (factor II) to ________ (factor IIa) which, in turn, leads to the thrombin-catalyzed cleavage of fibrinogen to ______ (the clot).
Factor X , thrombin, fibrin
Calcium is transported in the blood as...
Free or ionized calcium (50%) Bound to proteins such as albumin or pre-albumin (40%) Complexed with sulfate, phosphate or citrate (10%).
When a protective barrier of the body such as the epithelial layer of the skin or the GI tract or the endothelial layer of the blood vessels is breached, the underlying tissue such as collagen is exposed. Once the circulating factors such as factor XII or XI come into contact (adsorbed) with collagen or other underlying substances, these factors become activated (become active enzymes or proteases) and stimulate the clotting cascade in a stepwise fashion.
Intrinsic Pathway:
______________ absorption increases with a low dietary intake of calcium.
Lead
Osteoblasts produce two proteins:
Macrophage-stimulating factor Receptor activator of nuclear factor ĸ B ligand (RANKL)
Calcium is required for more body processes than bones and teeth...
Needed for glycogen synthesis and breakdown Needed for the removal of "the all important" intracellular second messenger cAMP via phophodiesterase Needed for the proper function of phospholipase A2 (releases ARA from second position of membrane phosphoplipid from use in the production of various eicosanoids (PGs, LTs and TXs) Needed to form the active dephosphorylated from of PDH complex.
_____________ activation allows for the assessment of total body calcium content
Neutron
Calcium supplements (<600 mg/d) of calcium from food will significantly decrease the absorption of _______-_________ iron within the intestinal cell (not at the brush border)
Non-Heme
called bone-building cells since they secrete..... when influenced by PTH, estrogen and calcitriol..... Collagen Other proteins Ground substances
Osteoblasts
___________ contain lysosomes that release acids and enzymes such as proteases and hydrolases that degrade bone and the matrix and dissolve the amorphous mineral complexes.
Osteoclasts
________________function to resorb/degrade previously made bone in response to PTH, calcitriol and calcitonin
Osteoclasts
___________ maintain the integrity of the bone surrounding them and, along with the osteoblasts and osteoclasts, maintain a communication network through long processes that are found in channels (canaliculi)
Osteocytes
_______________, both type I and type II, or loss of bone mass.
Osteoporosis
__________ increases the production of calcitriol in the kidney, increasing the renal tubular reabsorption of calcium via the vitamin D-dependent protein called calbindin D28k.
PTH
Low plasma ionized calcium (<8.5 mg/dL) (and magnesium) as sensed by the calcium-sensing receptors in the kidney tubule and parathyroid gland stimulates the secretion of _____ from the chief cells of the parathyroid gland and decreases the release of _______ from the parafollicular cells of the thyroid gland.
PTH, calcitonin
_____, alone or in conjunction with _________, causes an increase in extracellular calcium levels via effects on the kidneys, intestines and bone
PTH, calcitriol
Excessive calcium may decrease the absorption of...
Phosphorus (with a Ca:P ratio >3:1) Non-heme iron (as well as heme iron) Fatty acids
Both proteins (Macrophage-stimulating factor, Receptor activator of nuclear factor ĸ B ligand (RANKL))bind the RANK receptor on osteoclast precursor cells which cause the following:
Proliferation and differentiation of the osteoclast precursor cells into mature osteoclasts. Osteoclasts release enzymes and acids that breakdown bone, causing the release of calcium from the bone into the blood.
_____________ also decreases calcium secretions into the GI tract as well as increases the absorption of calcium in the gut
Protein
_____________ in children: the amount of calcium accretion per unit of bone matrix is deficient.
Rickets
______________ (500 mg/d) can increase the excretion of calcium (~10 mg/d) in the urine
Sodium
Urinary calcium excretion may be increased with....
Sodium protein caffeine boron-magnesium supplement
What dose Calcitonin do........
Suppresses PTH production and release Stimulates osteoblasts (bone forming cells) Inhibits osteoclasts (bone degrading cells) Decreases the reabsorption of calcium by the kidney May inhibit the production of vitamin D.....????
__________ or _______________ contractions of the extremities, muscle pain and paresthesia of the hands and feet are associated with low levels of serum ionized calcium (the active form of calcium in the blood).
Tetany or spasmodic
Demineralization for both cortical and trabecular bone Occurs in men & women >70 YOA Causes... o Age-related decreases in bone metabolism, particularly osteoblast activity o Decreased synthesis of calcitriol due to decrease renal function which occurs with aging(CKD, atherosclerosis, DM) Decreased 1-hydroxylase activity in the kidney, cannot form 1,25(OH)vitamin D3. o Decreased intestinal absorption of calcium (decrease acid secretion, Rx med effect, decrease vitamin D) o Other contributing factors: Habitually low calcium intake Increased serum parathyroid concentrations with aging (↑ bone resorption/bone demineralization)
Type II/Age-Related Osteoporosis
Excess intake of Vitamin ________ (Retinol but not Beta-carotene) stimulates osteoclast activity and decreases osteoblast activity. The result is decreased bone mineral density (BMD) and increased fracture risk
Vitamin A
Vitamin ______ deficiency stimulates osteoblast activity and decreases osteoclast activity. The result is excessive bone deposition and reduced bone degradation
Vitamin A
Vitamin _________ is necessary for bone metabolism, but too little or too much vitamin _____ will affect bone deposition and bone degradation, respectively
Vitamin A
After the need for intracellular calcium __________, the concentration of intracellular calcium returns to its normal level by a reversal of the events that caused it to increase: The stimulating neurotransmitter is degraded or the second messenger is inactivated. Calcium is pumped out of the cell via a calciummagnesium or calcium-sodium ATPase or the calcium is re-sequestered by the intracellular organelle (ER, mitochondria, nucleus) or binder (phosphate).
decreases
Populations with an increased need for calcium include:
o Those ingesting a high-fiber/high phytate diet o Those with fat malabsorption o Those who are immobilization o Those with a decreased transit time in the GI tract. o Those on long-term thiazide diuretic treatment for HTN.
Two other intestinal calcium transport systems
o Vasicular Transport System o Transcaltachia System
Three main types of bone cells: _______________, ______________, ________________
osteoblasts, osteocytes and osteoclasts:
PTH stimulates _________ in bone, promoting bone degradation and the release of calcium from bone and eventually into the plasma.
osteoclastsa.
The osteoblasts become embedded into the materials and become ____________. The differentiation of osteoblasts into ______________ occurs after they secrete the proteins and ground substances and after mineralization has occurred.
osteocytes
