Lecture Outline #9: Hormonal Control of Calcium Homeostasis
I. INTRODUCTION (Fig. A) (Fig.
9.1)
1. In earlier days, surgeons were unaware of the parathyroids [parathyroid], and thyroidectomies caused a Ca++ deficiency that resulted in irregular muscle contractions, tetanic cramps, poor nerve conduction, improper blood clotting, disruption of hormone signal transduction at receptors, and eventual death.
2. Ca++ is involved in control systems throughout the body. (a 70 kg person has 1 kg Ca++.)
3. Ca++ is actively transported across the intestinal mucosa and the renal tubules.
4. In plasma & fluids it is kept at 10 mg/100 ml--50% is free and 50% is albumin [albumin] bound.
5. Bone is the principal storage depot for Ca++.
II. THE NATURE OF BONE, BONE
MINERALS, AND BONE CELLS
1. Bone is constantly being formed, absorbed, and re-deposited throughout life.
2. The two principal bone minerals are Ca++ (whose general functions are outlined, above) and PO4, which is involved in cAMP, ATP, and phosphorylation. (renal regulation of PO4)
3. Ca++ and PO4 in high concentration precipitate to form hydroxyapatite [hydroxyapatite] in bone.
4. The four types of bone cells are: (Fig. B)
a. Osteogenic cells, which are stem cells that form a variety of other cells.
b. Osteoblasts (which resemble fibroblasts) synthesize and secrete osteoid proteins (mostly collagen) and polysaccharides that form the soft organic part of bone tissue.
(1) osteoblasts are most active in bone formation and re-deposition.
(2) osteoblasts cause alkalinity that promotes hydroxyapatite precipitation.
c. Osteocytes, which are transformed osteoblasts that have "buried" themselves in collagen and bone matrix, except for canaliculi through which they remain in contact with cytoplasmic processes of other osteocytes and osteoblasts.
d. Osteoclasts are multi-nucleated cells that reabsorb bone (by lysosomal enzymes) and release Ca++. (they are derivatives of large lymphocyte/macrophage)
(1) osteoclasts are most active in bone resorption and remodelling.
(2) osteoclasts secrete acids to promote release of Ca++ & PO4.
(NOTE: For more information on structure, formation and function of bone, click HERE.)
III.
FACTORS
THAT CONTROL Ca++ HOMEOSTASIS
A.
THE
PARATHYROID GLANDS AND PARATHYROID HORMONE
(Fig.
9.1)
1. The two pairs of parathyroids arise from embryonic endoderm, and imbed in the thyroid gland.
2. The chief cells secrete parathyroid hormone (PTH). (Oxyphil cells may be degenerated chief cells)
4. Initially, it is a 115 AA preproPTH, converted to 90 aa, then 84 aa in chief cell Golgi.
5. Low levels of circulating Ca++ increases PTH exocytosis by a complex negative-feedback system.
6. PTH functions to:
a. cause hyperplasia of osteoclasts.
b. couple with receptors on osteoclasts to increase cAMP and PLC (IP3 and DAG) (Fig. 9.10).
This signal transduction increases osteoclast activity and acid secretions from osteoclasts.
c. stimulate biosynthesis of 1-25-dihydroxy vitamin D3 by the kidneys.
d. enhance intestinal uptake of Ca++.
e. increase PO4 excretion across the proximal tubule (this favors Ca++ ionization).
f. increase renal distal tubule resorption of Ca++.
(NOTE: For a few more details about these actions of PTH, click HERE.)
B. SKIN, AND THE FORMATION OF ACTIVE VITAMIN D3
1. Epidermal cells (in the skin) obviously arise from the embryonic ectoderm.
2. They secrete a provitamin D (7-dehydrocholesterol) into the extracellular spaces. (Fig. 9.C)
3. UV radiation converst this into vitamin D3 (cholecalciferol).
4. In the liver, cholecalciferol is converted by 25-hydroxylase to 25-OH vitamin D3.
5. In the kidney, this is converted by 1a-hydroxylase to 25-OH vitamin D3.
6. Low blood Ca++ promotes PTH which stimulates renal 1a-hydroxylase. (Fig. 9.9)
a. It increases absorption of Ca++ and PO4 across the GI tract (mainly the large intestine).
b. Promotes CaBP (after 2 hours) to facilitate active transport of Ca++ across intestines (Fig. 9.9)
c. Even though it is important in bone growth, it acts synergistically with PTH to cause bone demineralization when circulating Ca++ is low.
d. It may promote renal resorption of Ca++ and PO4
e. It has innumberable other functions in metabolic processes.
8. A variety of factors control vitamin D biosynthesis.
C. “C” CELLS OF THE THYROID GLANDS AND CALCITONIN SECRETION
1. The parafollicular cells (also called “C” cells) arise from embryonic ectodermal (neural crest).
2. They develop around the thyroid follicles.
3. High blood Ca++ causes these “C” cells to release membrane-bound granules of calcitonin (CT).
4. Calcitonin consists of a 32 AA protein in most species.
(5. Not surprisingly, a CT gene-related peptide is also found in the nervous system.)
6. Gastrin, and to a lesser extent CCK, stimulates CT (in anticipation of Ca++ intake with food).
7. The functions of calcitonin include:
a. prevention of hypercalcemia by promoting bone deposition.
b. alters the morphology of osteoclasts—causing them to loose their ruffled borders and decreasing their lysosomal enzyme secretions.
c. CT is high during gestation and lactation—probably to protect maternal bones.
d. CT may inhibit the hypothalamic hunger center, or stimulate the satiety center, since it decreases food intake in rats and monkeys.