Calcium Homeostasis / PTH / Vitamin D

99% of the body's Ca²⁺ is present in bones

1% is required for fertilization, vision, muscle contraction, nerve conduction, blood clotting, exocytosis, cell division and the activity of many enzymes and hormones

The concentration of calcium in the cellular and extracellular fluids must be maintained at a constant value.

Resorption: the process of breaking down and assimilating (Ca²⁺ mobilization)

Reabsorption: the process of re-absorbing (absorbing again)

1,25(OH)₂D₃: Vitamin D (active form, 1,25 D)

PTH: Parathyroid hormone

CT: Calcitonin

Low Plasma Calcium: stimulates PTH release, and PTH acts to resorb Ca²⁺ from the pool in bone and to enhance renal re-absorption of Ca²⁺

High Plasma Calcium: stimulates CT secretion which lowers plasma calcium by inhibiting bone resorption

i) functions to raise plasma calcium via bone resorption and renal calcium reabsorption

ii) stimulates the metabolism of Vitamin D to its active hormonal form, 1,25(OH)₂D₃

i) promotes calcium absorption from the gut

ii) promotes calcium reabsorption from the kidney

iii) promotes calcium mobilization from bone via resorption

iv) enhances phosphate absorption by the intestine

Control of Blood Ca²⁺ and PO₄^3-:

Excessive PTH usually due to a Parathyroid Adenoma, breaks the feedback loops

Symptoms- renal stones, bone pain (due to increased bone resorption)

Lack of PTH (usually due to removal of the parathyroid gland along w/ the thyroid)

Symptoms- hypocalcemia

Treatment- large doses of 1,25(OH)₂D₃ to raise blood calcium through intestinal calcium absorption

 

PTH is an 84 A.A. peptide initially biosynthesized as prepro-PTH

PTH acts upon target cells primarily to increase cAMP via G_s

Kidney is the primary site of PTH action

PTH infusion will sharply increase urinary cAMP levels, as well as producing a marked increase in urinary phosphate levels (PTH inhibits renal phosphate reabsorption)

Symptoms: short stature, round face, abnormally short fingers and toes, subcutaneous calcification and mental deficiency

Cause: deficiency in the G_s protein that couples receptors to adenylate cyclase, G_s activity is only about 50% of normal

Since G_s couples many other hormone receptors to adenylate cyclase, TSH, glucagon etc, severely affected patients display resistance to these hormones as well.

It operates via receptors in bone that are coupled to adenylate cyclase through G_s and raise cAMP levels.

How can CT act on bone to lower Ca²⁺ resorption while PTH increases resorption when both function via G_s to raise cAMP???

CT raises cAMP in bone resorbing osteoclasts ----> inhibit their activity

PTH raises cAMP in osteoblasts ----> secrete resorptive factors ----> activate osteoclasts

Photosynthesis of Vitamin D₃:

Vitamin D itself does not act upon intestine, kidney and bone but must be bioactivated in the liver and kidney

The Bioactivation and Inactivation of Vitamin D₃:

1. It stimulates calcium absorption more rapidly than other forms of vitamin D.

2. It is more active on a molar basis than any other form.

3. it is produced in kidney in a regulated fashion, based on the need for calcium and/or phosphate.

4. It has specific receptors in intestine, bone and kidney.

5. It chemically resembles the steroid hormones.

Regulation of 1,25(OH)₂D₃ Production:

Note: When Ca²⁺, PO₄^3- and 1,25(OH)₂D₃ are elevated, 25(OH)D₃ is metabolized to 24,25(OH)₂D₃ an inactive metabolite.

1,25(OH)₂D₃ production is stimulated under the following conditions:

1. Low dietary calcium: PTH is secreted, which activates the 1-OHase in kidney to produce 1,25(OH)₂D₃.

2. Low dietary phosphate: direct enhancement of kidney 1-OHase.

3. Active growth in children: via growth hormone stimulation of 1-OHase.

4. Pregnancy and lactation: estrogens and prolactin increase renal 1,25(OH)₂D₃ output.

Biochemical Mode of 1,25(OH)₂D₃ Action:

The proposed mode of action for 1,25(OH)₂D₃ resembles the mode of action of the general class of thyroid/steroid hormones:

ii) mediation by a nuclear receptor

iii) stimulation of DNA transcription

iv) synthesis of functional proteins: Calcium Transporter (Ionophore), Ca-Binding Protein and Ca-ATPase.

Symptoms- delayed walking, severe rickets

Serum Chemistry- low Ca²⁺, high PTH and phosphate, high 25(OH)D₃, low 1,25(OH)₂D₃

Cause- defective 1-OHase enzyme in kidney

Treatment- physiologic replacement doses of 1,25(OH)₂D₃

Symptoms- rickets, bowing of lower extremities, hair loss

Serum Chemistry- low Ca²⁺, high PTH, normal 25(OH)D₃ and elevated 1,25(OH)₂D₃

Cause- target tissue resistance to 1,25(OH)₂D₃, receptor or post-receptor defect

Treatment- mega doses of 1,25(OH)₂D₃

. Affects over 27 million individuals in the U.S. and about 1.5 million fractures are . attributable to osteoporosis annually in people 45 and older.

. Of those women who live to age 90, 32% will suffer hip fracture.

. Cost of oteoporosis is $10 billion annually.