Calcium regulation, parathyroid hormone

Lecture 10

outer part

cortical (compact) bone

80% of skeletal mass

gives bone much of its strength

inner compartment

trabecular (cancellous) bone

20% of mass

made up of interconnected plates called trabeculae

trabeculae

sites of active remodeling

osteoid

bone is living tissue composed of organic extracellular matrix

bone

is impregnated with hydroxyapatite crystals are largely Ca3(PO4)2 salts

these stores may be mobilized

when plasma Ca falls

so bone remodeling is involved in Ca homeostasis

remodeling via

bone deposition/resorption

maintains skeletal strength and health

human skeleton

turns over every 10 years

osteoclasts

responsible for bone resorption (breakdown)

osteoblasts

responsible for laying down new bone

bone remodeling steps

1. osteoclast recruitment and activation

2. resorption and osteoblast recruitment

3. osteoblastic bone formation

4. completed remodeling cycle

RANK-L

made by osteoblast and bone marrow stromal cells

osteoclast precursor

cell death

dec bone mass

osteoclast

OPG osteoprotegerin

produces by marrow cells

inc bone mass

osteoblast

osteoblasts make

RANK-L and OPG

balance determines the outcome on bone mass

OPG low and RANK-L high

osteoclast favored

dec bone mass

OPG high and RANK-L low

osteoblast favored

inc bone mass

calcium be liberated

osteoclast and dec bone mass

hypocalcemia

dec Ca

inc Na influx

resting potential closer to threshold

inc neuromuscular excitability

spasm

hypercalcemia

inc Ca

dec neuromuscular excitability and car

excitation-contraction coupling

in cardiac and smooth muscle

stimulus-secretion coupling

Ca triggers exocytosis of NT and peptides

excitation-secretion coupling

pancreatic B-cells

membrane depolarization causes inc Ca entry and insulin secretion

maintenance of

tight junctions between cells

clotting of blood

Ca is a cofactor in clot formation

calcium homeostasis

controlled by hormones acting on bone

endocrine system regulates

plasma concentrations of inorganic electrolytes

Na, K, Ca, PO43-

main regulators

parathyroid hormone (PTH)

calcitonin

vitamin D

99% of calcium is

crystalline form in skeleton and teeth

bone is a reservoir of calcium

remaining 1%

is in extracellular fluid

plasma protein bound

ionized

complexed to organic ions

parathyroid hormone

stimulus: low serum Ca

origin: PTH gland

inc Ca

dec phosphate

vitamin D

stimulus: low serum Ca, low phosphate, PTH

origin: skin then metabolized in liver and kidney

inc Ca

inc phosphate

fibroblast growth factor 23

stimulus: high serum phosphate

origin: osteocytes in bone matrix

dec phosphate

calcitonin

stimulus: high Ca

origin: parafollicular C cells of thyroid gland

dec Ca

calcium

exchanges across osteocytic-osteoblastic bone membrane

parathyroid hormone (PTH)

released when serum Ca decrease

PTH

secreted by parathyroid glands

peptide hormone

metabolized by liver

metabolites cleared by kidney

responsive to

alteraction in Ca concentrations

low Ca

stimulate PTH secretion

high Ca

suppresses PTH synthesis and secretion

PTH producing cells

express an extracellular calcium-sensing receptor

Ca high

CaSR is activated

inhibiting the release of PTH

Ca low

CaSR is inactive

PTH is released

chronic hypocalcemia

stimulates proliferation of the PTH gland

leads to hyperplasia

type 1 PTH receptor

mediates PTH effects on Ca

GPCR

expressed on osteoclasts and osteoblasts

recognizes PTH and PTH-related peptide

type 2 PTH receptor

expressed on other tissues

specific to PTH

PTH

stimulates Ca release from bone

enhances osteoclast by stimulating RANK-L

stimulates reabsorption

of Ca in the kidney

inhibits

phosphate reabsorption

promotes phosphate excretion

stimulates

production of vitamin D

increases intestinal Ca reabsorption

inc Ca

negative feedback is exerted on PTH gland

vitamin d

pro hormone produced in the dermis in response to UV-B exposure

metabolized to active forms in liver then kidney

active hormone

1,25-(OH)2-D3

PTH stimulates

the synthesis of vitamin d

integrates stimulation of Ca homeostasis

vitamin d

enhances intestinal reabsorption of Ca

vitamin d stimulated

by hypocalcemia and hypophosphatemia, FGF-23 and low PTH

vitamin d inhibited

by hypercalcemia and hyperphosphatemia

vitamin d supplements

contain pro hormone

vitamin d receptor

member of steroid hormone receptor family

derives from cholesterol

in the intestine

it stimulates active intestinal transport of Ca in the duodenum

enabling Ca absorption

in bone

regulates osteoblasts/osteoclast function to favor the osteoclast path

through RANK

helps to increase plasma Ca

vitamin d promotes

intestinal absorption of phosphorus

fibroblast growth factor-23

regulates phosphate homeostasis

stimulated when phosphate is high

restores serum phosphate to physiological levels

phys of FGF-23

produced by osteocytes in bone matrix

effects are mediated by FGF receptors and co-receptor transmembrane protein, klotho

calcitonin

peptide hormone

produced by parafollicular C cells of thyroid gland

C cells

<0.1% of thyroid mass

distributed through the gland

hypercalcemia

stimulates the release of calcitonin

via CaSRs in C cells

calcitonin actions

lower serum Ca

rapidly released upon hypercalcemia

targets are bone and kidney

acts directly on osteoclasts (inhibitory) to block bone resorption

counterregulatory to PTH, vitamin D

pathophy calcitonin

medullary carcinoma of the thyroid- a C-cell neoplasm, accounting for 5-10% of thyroid malignancies