Unit 3 Physiology: Calcium Regulation (Leff)

CALCIUM AND PHOSPHATE BALANCE:

Calcium Distribution and Balance:
- Diet: take in ~1g Ca2+/day, majority leaves in feces (the rest is removed in the urine)
- Kidney: filters ~10g of Ca2+/day, most is reabsorbed
- Bone Formation and Resorption:
o There is a lot of activity going on throughout the day in terms of bone deposition
and resorption
o However, there is no net change in bone density as the two processes balance one
another
o Pathology occurs when theres an inbalance
Phosphate Distribution and Balance:
- Essentially the same type of regulation except for the fact that it is less tightly regulation
and more variation occurs in its concentration on a minute to minute basis in circulation
Relationships b/t ca2+ and PO43-
o Both required for bone mineralization
Hydroxyapatite crystals are composed of both ions [Ca10(PO4)6(OH)2]
o Reciprocal regulation of circulating levels
Kidney: PTH Ca2+ reabsorption but inhibits PO43- reabsorption
o Differential effects on PTH production
Elevated circulating Ca2+ suppresses PTH production, elevated PO43- stimulates
PTH production
Bone Structure:
- Organized into osteons
- Outer compact bone less active in terms of bone deposition and resorption
- Trabecular (spongy) bone more active in these processes
- Canaliculi involved in sensing stress and transmitting that information to more active parts
of the bone to modify resorption and deposition of bone
Maintenance of Bone Density:
- Under normal conditions, there is a balance between osteoblasts and osteoclasts activity
- Osteoblasts:
o Promote bone deposition (prefer to deposit bone at sites where osteoclasts were
just active)
o Stimulated directly by both PTH and vitamin Dform new bone by depositing Ca2+
and Pi
Vit D also stimulates differentiation of stem cells into osteoclast precursors
to form osteoclast
o Release several factors that affect osteoclast function:
M-CSF is a growth factor that stimulates differentiation of stem cells into
osteoclast precursors osteoclast
Produce cytokine IL-6 to stimulate osteoclast activity
Produce RANK ligand which stay on the surface of osteoblast cells
Osteoblast cells interact with osteoclast cells via RANK ligand
(osteoclast has RANK ligand receptors) and stimulates osteoclast
activities bone resorption
o Balance between the osteoclast and osteoblast actions. Both Vit D and PTH have
bone deposition and bone resorption activities
- Osteoclasts:
o Multinucleated cells that promote bone resorption (seal off a portion of the cell and
alter the environment of sealed off region)
o Osteoblast precursors stimulated to differentiate by vitamin D
Osteoclast Signaling:
- Involved multiple hormonal and local activities
- Has receptors for multiple molecules:
o Calcitonin: inhibits osteoclast activity
Receptor is coupled to a Gs protein (active PKA inhibits bone reabsorption)
o IL-6/RANK Ligand: bind receptor and promote bone resorption
o Osteoprotegrin: results in less osteoclast activity
Essentially the cytoplasmic domain of the RANK receptor
 Binds RANK ligand and prevents it from binding its receptor on the
osteoclast (cannot stimulate bone resportion)

PARATHYROID HORMONE:
Parathyroid Gland:
- Sense circulating levels of Ca2+
- Release Ca2+ in response to plasma Ca2+ (therefore, act to increase plasma Ca++)
Structure of PTH:
- Synthesized from a larger molecule (pre-pro PTH)
- Secreted PTH is 84AA long
- N terminus is the functional end of the hormone
o Teriparatide is a drug that mimics this end of the PTH molecule
Used in the treatment of osteoporosis because under some conditions
(sporadic/periodic release) PTH actually promotes bone building
Secretion of PTH:
- Ca2+ sensing receptor on the surface of parathyroid chief cell binds Ca2+ (senses levels in
blood)
- If Ca2+ levels increase:
o Receptor binds Ca2+, activates Gq mechanism of cell signalingactivates
PLCPIP2 IP3+DAG
o IP3 release of Ca2+ from the ER and increase intracellular levels of Ca2+
o This increase in Ca2+ INHIBITS vesicle docking and fusion, and PTH is no
longer released**(PTH synthesis is also inhibited)
o DAG activates PKC and contributes to the same pathway and prevents vesicle
fusion with cell membrane
PTH Action:
- Works to maintain circulating Ca2+levels (increases Ca2+ when low)
- Ca2+PTH release
- Direct effects:
o Bone: bone Ca2+ Resorption
o Kidney:
Kidney Tubule Ca2+ Reabsorption
enzyme for conversion of 25(OH)D3 1,25(OH)2D3 (active vitamin D3)
kidney tubule Pi reabsorption
- Indirect effects: due to Vit D
o Gut:Intestinal Ca2+ Reabsorption from dietary sources
o Bone: bone resorption
o Kidney: ca2+ reabsorption in tubules
VITAMIN D:
Synthesis:
- We can synthesize vitamin D in our skin using UV light
o 7-Dehydrocholesterol + UV Cholecalciferol
o Therefore, not really a vitamin unless there is a lack of UV light and we can no
longer produce it (at which point we would have to obtain it from the diet)
- No endocrine gland that produces it, but has hormone-like properties
- Cholecalciferol 25-(OH)-D3 in liver = Storage form
- 25-(OH)-D3 1,25-(OH)2-D3 (Active form) in kidneythis step is stimulated by PTH
- Vitamin D receptors are located almost everywhere in the body and therefore, their
function is not limited solely to Ca2+ regulation (other functions are not really well
understood)
Effects of Vit D
- Ca2+ & PO43-Absorption in the Gut:
- acts synergistically w/ PTH to Ca2+ reabsorption in kidney
- Directly acts to mobilize Ca2+ out of bone
- Thus overall effect of Ca2+ is bone mineralization
 Vit D regulates Ca2+ absorption in the gut
o A direct paracellular path for Ca2+ reabsorption thats not Vit D dependent
o Vit D controlled reabsorption of Ca2+ is under a Vit D receptor control.
Vitamin D acts like a steroid hormone, enters nucleus and alters transcription
of genes, resulting in the production of proteins required for the transport of
Ca2+ out of the gut
Proteins synthesized include:
Ca2+ channel (bring Ca2+ into intestinal cells from lumen)
Calbindin (Ca2+ binding protein that helps create a favorable Ca2+ gradient
allowing more Ca2+ to enter from lumen)
Ca2+ transporter (ATP dependent) to move it to the ISF
Ca2+/Na+ transporter (not ATP dependent)
Regulation of Phosphate Absorption:
o Promotes absorption of phosphate from intestine as well
o Behaves in a similar fashion to above:
o Alters gene transcription resulting in synthesis of proteins associated with
transport of phosphate out of the lumen and into the ISF (one transporter on each
side of the intestinal cell)

OTHER HORMONES AFFECTING CALCIUM METABOLISM:

Calcitonin: inhibits osteoclasts (slows bone resorption); complicated actions
Sex Steroids (testosterone and estrogen): promotes bone deposition
o Decrease in estrogen in menopause often causes osteoporosis in women
Glucocorticoids: promote bone resorption
PTH-related peptide (PTHrP): mimics PTH by physiological role is unclear

PATHOLOGICAL CONDITIONS OF CALCIUM METABOLISM:

Familial Hypercalcemic Hypocalciuria: inherited mutation in Ca2+ sensing receptor in
parathyroid cells that makes the receptors hyposensitive to Ca2+ (PTH suppression only occurs
at very high Ca2+ levels; very rare disease)
Osteoporosis
o Causes: reduced estrogen levels (primary cause), long-term glucocorticoid therapy,
inactivity, low Ca2+ intake or absorption, hyperparathyroidism, kidney disease (can
cause hypersecretion of Ca2+
o Treatments: hormone replacement therapy (Raloxifen; not used as much anymore
due to side effects), bisphosphonates, PTH (Forteo), calcitonin, exercise (weight-
bearing promotes bone deposition)
Rickets (Vitamin D Deficiency): common before food was fortified with vitamin D (very rare
now)
o Can be induced by some gastric bypass surgeries (remove areas that normal are
involved in fat soluble vitamin uptake)