Lecture 6: Calcium and Phosphate Homeostasis

What are the critical roles of calcium? [BACKGROUND]

• structural integrity

• muscle contraction

• cardiac action potential

• neurotransmission

• hormone secretion

• fertilization

What is the critical role of phosphate?

energy production

True or False: 18% of calcium turns over each year (adults). Ionized calcium levels are carefully controlled.

true

True or False: Phosphate isn’t as strictly regulated as calcium.

true

What are calcium levels regulated by?

• 1,25-dihydroxvitamin D

• parathyroid hormone (PTH)

• calcitonin

What are the 3 sites of Ca²⁺/P_i homeostasis?

• bone

• kidney

• intestine

What is the goal of calcium homeostasis?

to keep blood calcium levels in a specific range

What is the calcium stored by?

the bone

What is the calcium released by?

the bone

What is the calcium absorbed by?

the intestine

Where is calcium excreted by?

the intestine

What is the calcium reabsorbed by?

the kidney

What is the calcium excreted by?

the kidney

Practice drawing the calcium homeostasis diagram.

Review the following calcium homeostasis diagram.

What are the cells that make parathyroid hormone called?

Chief cells

What does the parathyroid gland do?

produces PTH

What type of hormone is PTH?

peptide hormone

What is the half-life of PTH?

short half-life of 4 min

What is the main function of PTH?

to raise blood Ca²⁺ levels

What inhibits PTH release?

circulating Ca²⁺

What does Ca²⁺-sensing GPCR activate? What does this lead to?

phospholipase C (PLC)—leading to the release of intracellular Ca²⁺ and activation of PKC

True or False: PTH regulates calcium through a negative feedback loop.

true

What does activated PKC and calcium inhibit?

PTH synthesis and secretion

What are the systemic effects of PTH? [BACKGROUND]

• bone releases calcium

• kidney returns calcium

• kidney makes vitamin D3

• intestine absorbs more calcium

Where is calcitonin produced and by which cells?

the thyroid proper; C-cells

What type of hormone is calcitonin?

peptide hormone

What type of receptors does calcitonin bind to?

GPCRs

What causes the release of calcitonin?

rising extracellular calcium

What does calcitonin do?

acts on the bone to inhibit breakdown and promote reabsorption to lower the extracellular calcium levels in the blood

True or False: There is an inverse relationship between calcitonin and PTH.

true

What type of hormone is vitamin D3?

steroid hormone

What is vitamin D3 bound by?

vitamin D binding protein (DBP)

What is the half-life of vitamin D3?

long half-life of 1-3 days

Which organ is important for vitamin D3?

the kidney

Which type of receptor is vitamin D receptor (VDR)?

a nuclear receptor

What does vitamin D signal transduction affect?

affects gene transcription including Ca²⁺ channels, pumps, and calcium binding proteins (like calbindin)

Briefly describe cortical bone.

• outer layer of bone

• 80% of bone mass

Briefly describe trabecular bone.

• inner layer of bone

• 20% of bone mass

• site of action

True or False: Bone remodeling and turnover is essential for bone strength and adaptation to changes in weight bearing.

true

What are bone cell types?

• osteoblasts

• osteogenic cells

• osteocytes

• osteoclasts

What are osteogenic cells?

cells that develop into osteoblasts

What do osteoblasts do?

forms bone matrix

Which stem cells do osteoblasts come from?

mesenchymal stem cells

What to osteocytes do?

maintains bone tissue

What do osteoclasts do?

functions in reabsorption, the breakdown of bone matrix

Which stem cells do osteoclasts come from?

hematopoietic stem cells

True or False: PTH directly affects osteoblasts to produce osteoclasts and make osteoclasts more active.

true

What do osteoblasts do?

synthesize and secrete proteins and to form a matrix (osteoid)

Which proteins do osteoblasts synthesize and secrete?

• type 1 collagen

• osteocalcin

• osteonectin

Osteoblasts deposit calcium and phosphate from which fluid into where?

from extracellular fluid and intracellular stores into the matrix

What stimulates osteoblasts to make M-CSF? What does this do?

PTH and vitamin D—increasing osteoclast number

What does PTH stimulate the release of? What does this do?

IL-6 and RANK ligand from osteoblast to osteoclast—stimulating bone reapsorption and calcium release

What do osteoclasts do?

break down bone by secreting H+ and proteases to dissolve bone mineral and hydrolyze matrix proteins

Which proteins stimulate bone reabsorption?

IL-6 and RANK ligand

What inhibits bone reabsorption?

calcitonin

How does the kidney cause calcium-reabsorption?

• stimulating insertion of calcium channels in the luminal membrane

• stimulating calcium efflux mechanism in the basolateral membrane

Which location of the kidney and in which cell does PTH act on?

nephron; principal cell

How does the kidney cause phosphate excretion? What does this release?

activating phosphorylation of NERF—releasing the sodium phosphate cotransporter (PT) to be degraded

How does the kidney stimulate vitamin D synthesis?

stimulating expression and activation of P450 1-alpha-hydrolase

Where does phosphate excretion and vitamin D synthesis occur?

renal proximal tubule cell

How does the vitamin D stimulate the intestine to synthesize proteins involved in calcium transport?

• calcium from intestinal lumen enters the cell through channel

• calcium binds to calbindin

• calcium is extruded across the membrane through Ca pump and Na-Ca exchanger

Which cells in the intestine deal with calcium absorption?

intestinal enterocytes

How does vitamin D cause phosphate absorption in the intestine?

• phosphate from intestinal lumen enters the cell through Na/P cotransporter

• phosphate is extruded across the basolateral membrane

What is hypercalcemia?

high blood calcium

What are the two main conditions that lead to hypercalcemia?

• PTH tumors (primary hyperparathyroidism)

• bone tumors (metastasis, multiple myeloma)

What is hypocalcemia?

low blood calcium

What causes hypocalcemia?

• inactivating mutation in the vitamin D receptor

• insufficient exposure to sunlight without supplementation (most common cause)

• secondary hyperparathyroidism

• GI diseases that interrupt vitamin D absorption

• hypoparathyroidism

What is secondary hyperparathyroidism caused by?

impaired vitamin D synthesis by the kidney

What can cause hypoparathyroidism?

surgery and congenital malformation

True or False: PTH levels are high → hyperparathyroidism. PTH levels are low → hypoparathyroidism. PTH levels don’t always equate to a certain calcium level in regard to clinical manifestations.

true

What conditions also can cause hyperparathyroidism?

• hypercalcemia

• kidney stones

• hypophosphatemia

• bone demineralization

What can hypocalcemia lead to?

• increased neuromuscular excitability

• tetany

• Trousseau’s sign (hand position)

• paresthesia (pins and needles)

• hyperventilation

• convulsions

What can cause hypocalcemia?

• hereditary deficiency of VitD3 receptor

• impaired synthesis of vitamin D by the kidney

• GI diseases that interrupt Vitamin D absorption

• living in the dark without dietary Vitamin D supplementation

• hypoparathyroidism due to surgery and congenital malformation

What can vitamin D deficiency cause in children and adults?

• children: rickets (bone has abnormal amounts of unmineralized osteoid)

• adults: osteomalacia (decline in bone strength, prone to back pain and bone fractures)