Endocrine Control of Ca2+ Homeostasis
- Many of the hormones of the body control functions that, though important, are not necessarily vital for survival, such as growth.
- By contrast, some hormones control functions so vital that the absence of the hormone would be catastrophic, even life threatening.
- One such function is calcium homeostasis.
- Calcium exists in the body fluids in its soluble, ionized form (Ca2+) and bound to proteins.
- For simplicity in this chapter, we will refer hereafter to the physiologically active, ionic form of Ca2+.
- Extracellular Ca2+ concentration normally remains within a narrow homeostatic range.
- Large deviations in either direction can disrupt neurological and muscular activity, among others.
- For example, a low plasma Ca2+ concentration increases the excitability of neuronal and muscle plasma membranes.
- A high plasma Ca2+ concentration causes cardiac arrhythmias and depresses neuromuscular excitability via effects on membrane potential.
11.20 Effector Sites for Ca2+ Homeostasis
- Ca2+ homeostasis depends on the interplay among bone, the kidneys, and the gastrointestinal tract.
- The activities of the gastrointestinal tract and kidneys determine the net intake and output of Ca2+ for the entire body and, thereby, the overall Ca2+ balance.
- In contrast, interchanges of Ca2+ between extracellular fluid and bone do not alter total-body balance but instead change the distribution of Ca2+ within the body.
- Approximately 99% of total-body calcium is contained in bone.
- Therefore, the movement of Ca2+ into and out of bone is critical in controlling the plasma Ca2+ concentration.
- Bone is a connective tissue made up of several cell types surrounded by a collagen matrix called osteoid, upon which are deposited minerals, particularly the crystals of calcium, phosphate, and hydroxyl ions known as hydroxyapatite.
- In some instances, bones have central marrow cavities where blood cells form.
- Approximately one-third of a bone, by weight, is osteoid, and twothirdsis mineral (the bone cells contribute negligible weight).
The three types of bone cells involved in bone formation and breakdown
- The three types of bone cells involved in bone formation and breakdown are osteoblasts, osteocytes, and osteoclasts.
- Osteoblasts: are the bone-forming cells. They secrete collagen to form a surrounding matrix, which then becomes calcified, a process called mineralization.
- Osteocytes: Once surrounded by calcified matrix, the osteoblasts are called osteocytes. The osteocytes have long cytoplasmic processes that extend throughout the bone and form tight junctions with other osteocytes.
- Osteoclasts: are large, multinucleated cells that break down (resorb) previously formed bone by secreting hydrogen ions, which dissolve the crystals, and hydrolytic enzymes, which digest the osteoid.
Throughout life, bone is constantly remodeled by the osteoblasts (and osteocytes) and osteoclasts working together.
- Osteoclasts resorb old bone, and then osteoblasts move into the area and lay down new matrix, which becomes mineralized.
- This process depends in part on the stresses that gravity and muscle tension impose on the bones, stimulating osteoblastic activity.
- Many hormones, as summarized in Table 11.6, and a variety of autocrine or paracrine growth factors produced locally in the bone also have functions.
- Of the hormones listed, only parathyroid hormone is controlled primarily by the plasma Ca2+ concentration.
- Nonetheless, changes in the other listed hormones have important influences on bone mass and plasma Ca2+ concentration.
- The kidneys filter the blood and eliminate soluble wastes.
- In the process, cells in the tubules that make up the functional units of the kidneys recapture (reabsorb) most of the necessary solutes that were filtered, which minimizes their loss in the urine.
- Therefore, the urinary excretion of Ca2+ is the difference between the amount filtered into the tubules and the amount reabsorbed and returned to the blood.
- The control of Ca2+ excretion is exerted mainly on reabsorption. Reabsorption decreases when plasma Ca2+ concentration increases, and it increases when plasma Ca2+ decreases.
- The hormonal controllers of Ca2+ also regulate phosphate ion balance. Phosphate ions, too, are subject to a combination of filtration and reabsorption, with the latter hormonally controlled.
- The absorption of solutes such as Na+ and K+ from the gastrointestinal tract into the blood is normally about 100%.
- In contrast, a considerable amount of ingested Ca2+ is not absorbed from the small intestine and leaves the body along with the feces.
- Moreover, the active transport system that achieves Ca2+ absorption from the small intestine is under hormonal control.
- Therefore, large regulated increases or decreases can occur in the amount of Ca2+ absorbed from the diet. Hormonal control of this absorptive process is the major means for regulating total-body-calcium balance,as we see next.
11.21 Hormonal Controls
- The two major hormones that regulate plasma Ca2+ concentration are parathyroid hormone and 1,25-dihydroxyvitamin D.
- A third hormone, calcitonin, has a very limited function in humans, if any.
Ca2+ hormones: Parathyroid Hormone
- Bone, kidneys, and the gastrointestinal tract are subject, directly or indirectly, to control by a protein hormone called parathyroid hormone (PTH), which is produced by the parathyroid glands.
- These endocrine glands are in the neck, embedded in the posterior surface of the thyroid gland, but are distinct from it.
- PTH production is controlled by extracellular Ca2+ acting directly on the secretory cells via a plasma membrane Ca2+ receptor.
- Decreased plasma Ca2+ concentration stimulates PTH secretion, and an increased plasma Ca2+ concentration does just the opposite.
PTH exerts multiple actions that increase extracellular Ca2+ concentration, thereby compensating for the decreased concentration that originally stimulated secretion of this hormone
- 1. It directly increases the resorption of bone by osteoclasts, which causes calcium (and phosphate) ions to move from bone into extracellular fluid.
- 2. It directly stimulates the formation of 1,25-dihydroxy vitamin D (described in detail shortly), which then increases intestinal absorption of calcium (and phosphate) ions. Thus, the effect of PTH on the intestines is indirect.
- 3. It directly increases Ca2+ reabsorption in the kidneys, thereby decreasing urinary Ca2+ excretion.
- 4. It directly decreases the reabsorption of phosphate ions in the kidneys, thereby increasing their excretion in the urine.
- This keeps plasma phosphate ions from increasing when PTH causes an increased resorption of both calcium and phosphate ions from bone, and an increased production of 1,25-dihydroxyvitamin D leading to increased calcium and phosphate ion absorption in the intestine.
11.21 Hormonal Controls- 1,25-Dihydroxyvitamin D
- The term vitamin D denotes a group of closely related compounds.
- Vitamin D3 (cholecalciferol) is formed by the action of ultraviolet radiation from sunlight on a cholesterol derivative (7-dehydrocholesterol) in skin.
- Vitamin D2 (ergocalciferol) is derived from plants. Both can be found in vitamin pills and enriched foods and are collectively called vitamin D.
- Because of clothing, climate, and other factors, people are often dependent upon dietary vitamin D. For this reason, it was originally classified as a vitamin.
- Regardless of source, vitamin D is metabolized by the addition of hydroxyl groups, first in the liver by the enzyme 25-hydroxylase and then in certain kidney cells by 1-hydroxylase.
- The end result of these changes is 1,25-dihydroxyvitamin D [abbreviated 1,25-(OH)2D], the active hormonal form of vitamin D.
The major action of 1,25-dihydroxyvitamin D + control
- The major action of 1,25-(OH)2D is to stimulate the intestinal absorption of Ca2+.
- Thus, the major consequence of vitamin D deficiency is decreased intestinal Ca2+ absorption, resulting in decreased plasma Ca2+.
- The blood concentration of 1,25-(OH)2D is subject to physiological control.
- The major control point is the second hydroxylation step that occurs primarily in the kidneys by the action of 1-hydroxylase, and which is stimulated by PTH.
- Because a low plasma Ca2+ concentration stimulates the secretion of PTH, the production of 1,25-(OH)2D is increased as well under such conditions. Both hormones work together to restore plasma Ca2+ to normal.
Ca2+ hormones- Calcitonin
- Calcitonin is a peptide hormone secreted by cells called parafollicular cells that are within the thyroid gland but are distinct from the thyroid follicles.
- Calcitonin decreases plasma Ca2+ concentration, mainly by inhibiting osteoclasts, thereby reducing bone resorption.
- Its secretion is stimulated by an increased plasma Ca2+ concentration, just the opposite of the stimulus for PTH.
- Unlike PTH and 1,25-(OH)2D, however, calcitonin has no function in the normal day-to-day regulation of plasma Ca2+ in humans.
- It may be a factor in decreasing bone resorption when the plasma Ca2+ concentration is very high.
11.22 Metabolic Bone Diseases: rickets and osteomalacia
- Various diseases reflect abnormalities in the metabolism of bone.
- Rickets (in children) and osteomalacia (in adults) are conditions in which mineralization of bone matrix is deficient, causing the bones to be soft and easily fractured.
- In addition, a child suffering from rickets is typically severely bowlegged due to weight bearing on the weakened developing leg bones.
- A major cause of rickets and osteomalacia is deficiency of vitamin D
11.22 Metabolic Bone Diseases: osteoporosis
- In contrast to these rickets and osteomalacia, in osteoporosis, both matrix and minerals are lost as a result of an imbalance between bone resorption and bone formation.
- The resulting decrease in bone mass and strength leads to an increased fragility of bone and the incidence of fractures.
- Causes: Osteoporosis can occur in people who are immobilized (“disuse osteoporosis”), in people who have an excessive plasma concentration of a hormone that favors bone resorption, and in people who have a deficient plasma concentration of a hormone that favors bone formation.
- It is most commonly seen, however, with aging. Everyone loses bone as he or she ages, but osteoporosis is more common in elderly women than men. The major reason for this is that menopause removes the antiresorptive effect of estrogen.
- Prevention is the focus of attention for osteoporosis.
11.22 Metabolic Bone Diseases: osteoporosis prevention + treatment
- Treatment of postmenopausal women with estrogen or its synthetic analogs is effective in reducing the rate of bone loss, but longterm estrogen replacement can have serious consequences in some women (e.g., increasing the likelihood of breast cancer).
- A regular weight-bearing exercise program, such as brisk walking and stair climbing, is also helpful.
- Adequate dietary Ca2+ intake and vitamin D intake throughout life are important to build up and maintain bone mass.
- Several substances also provide effective therapy once osteoporosis is established.
- Most prominent is a group of drugs called bisphosphonates that interfere with the resorption of bone by osteoclasts.
- Other antiresorptive substances include calcitonin and selective estrogen receptor modulators (SERMs), which, as their name implies, act by interacting with (and activating) estrogen receptors, thereby compensating for the low estrogen after menopause.
Hypercalcemia- Primary hyperparathyroidism
- Hypercalcemia: abnormally high plasma Ca2+ concentrations.
- A relatively common cause of hypercalcemia is primary hyperparathyroidism. This is usually caused by a benign tumor (known as an adenoma) of one of the four parathyroid glands.
- These tumors are composed of abnormal cells that are not adequately suppressed by extracellular Ca2+.
- As a result, the adenoma secretes PTH in excess, leading to an increase in Ca2+ resorption from bone, increased kidney reabsorption of Ca2+, and the increased production of 1,25-(OH)2D from the kidney. The increased 1,25-(OH)2D results in an increase in Ca2+ absorption from the small intestine.
- Primary hyperparathyroidism is most effectively treated by surgical removal of the parathyroid tumor.
Hypercalcemia- other causes
- Certain types of cancer can lead to humoral hypercalcemia of malignancy. The cause of the hypercalcemia is often the release of a molecule that is structurally similar to PTH, called PTH-related peptide (PTHrp), that has effects similar to those of PTH.
- This peptide is produced by certain types of cancerous cells (e.g., some breast-cancer cells).
- However, authentic PTH release from the normal parathyroid glands is decreased due to the suppression of parathyroid gland function by the hypercalcemia caused by PTHrp released from the cancer cells.
- The most effective treatment of humoral hypercalcemia of malignancy is to treat the cancer that is releasing PTHrp. In addition, drugs such as bisphosphonates that decrease bone resorption can also provide effective treatment
Finally, excessive ingestion of vitamin D can lead to hypercalcemia,
as may happen in some individuals who consume vitamin D supplements far in excess of what is required.
Regardless of the cause, hypercalcemia causes significant symptoms
primarily from its effects on excitable tissues. Among these symptoms are tiredness
with muscle weakness
, as well as nausea
(due to effects on the GI tract
Hypocalcemia: primary hypoparathyroidism and pseudohypoparathyroidism
Resistance to the effects of PTH in target tissue
- Hypocalcemia: abnormally low plasma Ca2+ concentrations.
- Hypocalcemia can result from a loss of parathyroid gland function (primary hypoparathyroidism).
- One cause of this is the removal of parathyroid glands, which may occur (though rarely) when a person with thyroid disease has his or her thyroid gland surgically removed.
- Because the concentration of PTH is low, 1,25-(OH)2D production from the kidney is also decreased. Decreases in both hormones lead to decreases in bone resorption, kidney Ca2+ reabsorption, and intestinal Ca2+ absorption.
) can also lead to the symptoms of hypoparathyroidism
, even though in such cases PTH concentrations in the blood tend to be elevated.
This condition is called pseudohypoparathyroidism
Hypocalcemia: secondary hyperparathyroidism
- Another interesting hypocalcemic state is secondary hyperparathyroidism.
- Failure to absorb vitamin D from the intestines, or decreased kidney 1,25-(OH)2D production, which can occur in kidney disease, can lead to secondary hyperparathyroidism.
- The decreased plasma Ca2+ that results from decreased intestinal absorption of Ca2+ results in stimulation of the parathyroid glands.
- Although the increased concentration of PTH does act to restore plasma Ca2+ toward normal, it does so at the expense of significant loss of Ca2+ from bone and the acceleration of metabolic bone disease.
- The symptoms of hypocalcemia are also due to its effects on excitable tissue. It increases the excitability of nerves and muscles, which can lead to CNS effects (seizures), muscle spasms (hypocalcemic tetany), and neuronal excitability.
- Long-term treatment of hypoparathyroidism involves giving calcium salts and 1,25-(OH)2D or vitamin D