Regulation of Ca2+ and Phosphate (Sayner)

(Sayner)

Extracellular calcium is under tight ________ control

Endocrine

Calcium intake via the intestine is dependent upon _____

Vitamin D

Calcium exchange between the intestine, kidney, and bone is ______ regulated.

hormone

Whole body daily calcium turnover

175 mg/day net uptake and 175 mg/day urine excretion

Distribution of total body calcium

Hypocalcemia <____ mg/dL

8.5

Hypercalcemia > __ mg/dL

10.6 symptomatic around 11.5

Which form of calcium is important for PTH regulation?

Free plasma calcium

Hypercalcemia especially above 11.5

99 of calcium is stored in ____

Bone

hydroxyapatite crystals

Within cytoplasm, calcium concentration is

Low

Whole body daily phosphate turnover

Net uptake 900 mg/day

Net loss from urine 900 mg/day

Phosphate uptake in the small intestines is dependent upon _____.

Vit D

Stored in bone and soft tissue.

Phosphate

Distribution of total body phosphate

Calcium blue

Phosphate orange

distribution

2.5 – 4.5 mg/dL is total plasma ______

phosphate

4.4 – 5.2 mg/dL is _____ plasma calcium

Free

8.5 – 10.6 mg/dL is total plasma _____

calcium

(Stones, bones, moans and groans) nausea, vomiting, abdominal or flank pain, constipation, altered mental status, headache, confusion, depression, weakness, myalgias, arthralgias, polyuria, polydipsia, and nocturia.

Hypercalcemia

Severe hypercalcemia can cause ____

Coma

Physical exam findings include hypertension, bradycardia, hyperreflexia, and tongue fasciculations.

Hypercalcemia

increased intestinal calcium absorption in response to elevated PTH levels

PTH-mediated hypercalcemia

Acute _______– symptoms include: syncope, congestive heart failure, numbness and tingling, muscle spasms and tetany, bronchospasm and wheezing, laryngospasm and dysphagia, irritability, depression, fatigue, and seizures.

hypocalcemia

Chronic ________ can lead to coarse hair, brittle nails, psoriasis, dry skin, pruritus, poor dentition, and cataracts.

hypocalcemia

The most common physical exam findings include neural hyperexcitability, psychological disturbances, and cardiac arrhythmias.

Hypocalcemia

The Chvostek and Trousseau signs are indicative of ______ states.

Hypocalcemic

Regulation of extracellular calcium is under tight endocrine control:

PTH

Vitamin D

Fibroblast growth factor 23 (FGF-23)

Calcitonin

Estrogen and glucocorticoids

PTH affects on

Bone:

Kidney:

resorption - osteoblast-mediated regulation of osteoclast activity – ↑ serum calcium

↑calcium reabsorption, ↓phosphate reabsorption, ↑vitamin D

PTH → Bone →

resorption - osteoblast-mediated regulation of osteoclast activity – ↑ serum calcium

PTH to kidney → ______ calcium reabsorption, → _______ phosphate resorption → ______ vitamin D

Increased

Decreased

Increased

PTH secreted by ____ cells of the parathyroid gland

Chief

Parathyroid gland

Thyroid gland with parathyroid gland

sensor for free Ca2+

Chief cells

Parathyroid gland often surrounded by _____ tissue.

adipose

Normal blood levels of ionized/free calcium inhibit PTH secretion via ______ on Chief cells.

calcium sensing receptor (CaSR)

As serum free calcium levels ____, inhibition of chief cells is lost and PTH secreted.

Drop

______ calcium binds to calcium sensing receptor (CaSR) on Chief cells. CaSR is coupled through ___ signaling and elevation of calcium to inhibit secretion of ___.

High

Gq

PTH

Gq – PLC- PIP2- DAG + IP3 – Calcium inhibits secretion of PTH vacuoles

Calcium inhibition of PTH synthesis and release

PTH processing

PTH Short __-terminal active fragment (half-life 4 minutes – breakdown in the kidney).

N

PTH Long __-terminal inactive fragment (longer half life so continues to circulate).

C

Active PTH is proteolytically cleaved secretory vesicles (chief cells) and ____(circulation) into 2 fragments

liver

PTH is synthesized in the ___

ER

PTH is broken down in the

Kidney

Both the full length (84 peptide) and the short N-terminal fragment – bind PTH-R_

1

PTH-R1 is expressed on _____ and _____

Bone and Kidney

______ reside on the surface of bone and secrete the unmineralized matrix (osteoid) and regulate mineralization of bone.

Osteoblast

Mesenchymal stem cells -> ______ -> osteocytes

Osteoblasts

Cell types of bone

Bone is type __ collagen

1

Bone calcium phosphate ratio ___/___

1/0.7

Cancellous (trabecular) bone is turned over more _____ than compact bone

Rapidly

resorb bone tissue (removal of bone tissue and release of calcium and phosphate)

Osteoclast

Multinucleated for Howships lacuna where absorption takes place

Osteoclast

Osteoclasts

Acts via osteoblasts to increase RANK-RANKL and decrease OPG

PTH

PTH bind PTH-R1 expressed on ________– activates Gs signaling to increase cAMP

osteoblasts

Increases expression of ______ and decrease ___, thereby increasing osteoclastogenesis and bone resorption.

RANK-L

OPG

PTH inhibits ______ synthesis by osteoblasts and promotes release of proteases.

collagen

______ are derived from hematopoetic stem cells

Osteoclasts

When RANK is engaged by it’s receptor RANK-ligand this promotes the differentiation of the precursor into its mature form ________

Osteoclast

While engagement of RANK-L with the receptor activates differentiation, there is a decoy pathway whereby ____, released from ______, binds to RANK and inhibits its interaction with the ligand thereby preventing _______ differentiation.

OPG

Osteoblasts

Osteoclast

During maturation ____ is necessary for osteoclast differentiation and activation

RANK

___ decoy receptor can bind RANKL so it cannot bind RANK

OPG

Increase ___ decreased activation and differentiation of osteoclast- less bone breakdown

OPG

_____ is on the osteoblasts increases expression of rank L and decreased OPG promoting bone resorption

PTH-R1

RANK ligand ______ osteoclast differentiation

Increases

OPG ______ osteoclast differentiation

Decreases

PTH-R1 is on the osteo_last and stromal cells

B

OPG is produced by the ________

Osteoblasts

Howship’s lacuna

Osteoclasts

In a condition of low free calcium, _________ release of PTH acts on osteoblasts to promote osteoclast differentiation and activity

persistent/continuous

____________ PTH bone synthesis – anabolic effect - increases bone density

Intermittent/pulsatile

Why is teriparatide used for osteoporosis if it is a recombinant PTH?

Because PTH in intermittent or pulsatile releases actually increases bone density

PTH has _____ effects in the intestines.

Indirect

Since the effects of PTH in the kidney regulate vitamin D synthesis which in turn regulates calcium absorption in the intestines

In kidney reabsorption of calcium from the lumen of the ____ back into the blood

distal convoluted tubule DCT

____ regulation of calcium primarily occurs in the thick ascending limb (TAL), distal convoluted tubule (DCT) and connecting tubule

PTH

In the kidney, PHT binding to the PTH-R1 - coupled to adenylyl cyclase via G⍺s to increase cAMP, activate PKA and the transcription factor ___

CREB

increases calcium channel gene expression in kidneys

CREB

PTH regulation of calcium reabsorption

PTH acts on the proximal (PCT) to inhibit _______ reabsorption to prevent unwanted calcium phosphate crystal formation.

phosphate

PTH increases renal phosphate excretion

____ promotes internalization of phosphate transporters

PTH

Binding of the PTH-R1 in kidney ___ leads to internalization of phosphate transporters.

PCT

Phosphate Thrashing Hormone

PTH

PTH in PCT of kidney stimulates vitamin D production by increasing ________ expression which hydroxylates inactive 25-hydroxycholecalciferol to the active form of vitamin D – 1,25 hydroxycholecalciferol (1,25 (OH)2D3, calcitriol)

1⍺-hydroxylase

Low phosphate also _______ 1⍺-hydroxylase to increase active vitamin D, while high phosphate and elevated levels of vitamin D _______ 1⍺-hydroxylase.

increase

inhibit

Since vitamin D regulates calcium and phosphate absorption in the intestines, PTH is considered to have ______ effects on the intestines.

Indirect

Where does vitamin D stimulation due to PTH happen in the kidney?

PCT

PTH increases vitamin D

Which is more active 25 hydroxycholecalciferol or calcitriol?

calcitriol

Control of plasma calcium PTH

Control of plasma phosphate PTH

Vitamin D_ (ergocalciferol) – Dietary vegetables

Vitamin D_ (cholecalciferol):

• Dietary intake (deep water fish, eggs, fortified milk)

• Synthesis from 7-dehydrocholesterol – requires UV light.

2

3

Vitamin D2 and D3 → calcitriol

1 alpha hydroxylase

Both calcitriol and 25-hydroxycholecalciferol bind to the_____ receptor.

Vit D

Normal plasma calcitriol ____-__ pg/mL

20-60

Vitamin D _____ 1⍺-hydroxylase

inhibits