Functional Anatomy of the Thyroid and Parathyroid Glands The thyroid gland is located in the neck, in close approximation to the first part of the trachea. In humans, the thyroid gland has a "butterfly" shape, with two lateral lobes that are connected by a narrow section called the isthmus. Most animals, however, have two separate glands on either side of the trachea. Thyroid glands are brownish-red in color. Close examination of a thyroid gland will reveal one or more small, light-colored nodules on or protruding from its surface - these are parathyroid glands (meaning "beside the thyroid"). The image shows a canine thyroid gland and one attached parathyroid gland. Occasionally, a person is born with one or more of the parathyroid glands embedded in the thyroid, the thymus, or elsewhere in the chest. In most such cases, however, the glands function normally. Though their names are similar, the thyroid and parathyroid glands are entirely separate glands, each producing distinct hormones with specific functions. Parathyroid hormone (PTH) PTH is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid. This hormone is secreted from cells of the parathyroid glands and finds its major target cells in bone and kidney. Another hormone, parathyroid hormone-related protein, binds to the same receptor as parathyroid hormone and has major effects on development. Parathyroid hormone Like most other protein hormones, PTH is synthesized as a preprohormone. After intracellular processing, the mature hormone is packaged within the Golgi into secretory vesicles, the secreted into blood by exocytosis. PTH is secreted as a linear protein of 84 aa. Although the 4 parathyroid glands are quite small- have a very rich blood supply. IMPORTANT- they are required to monitor the calcium level in the blood 24 hours a day. As the blood filters through the parathyroid glands, they detect the amount of calcium present in the blood and react by making more or less parathyroid hormone (PTH). IMPORTANT- they are required to monitor the calcium level in the blood 24 hours a day. When the calcium level in the blood is too low, the cells of the parathyroids sense it and make more PTH Once PTH is released into the blood, it circulates to act in a # of places to increase the amount of calcium in the blood. When the calcium level in the blood is too high, the cells of the parathyroids make less PTH (or stop making it altogether), thereby allowing calcium levels to decrease. This feed-back mechanism runs constantly, thereby maintaining calcium (and PTH) in a very narrow "normal" range. In a normal person with normal parathyroid glands, their parathyroid glands will turn on and off dozens of times per day...in an attempt to keep the calcium level in the normal range so our brain and muscles function properly. Physiologic Effects of Parathyroid Hormone Function for PTH is straightforward: if calcium ion concentrations in extracellular fluid fall below normal, bring them back within the normal range. In conjunction with increasing calcium concentration, the concentration of phosphate ion in blood is reduced. Parathyroid Hormone Receptors PTH and its cousin parathyroid hormone-related protein (PTHrP) are critical controllers of calcium and phosphorus balance. The receptors for these two hormones are of high interest to drug companies, because such understanding may facilitate development of antagonists for treatment of a number of important diseases, including osteoporosis and hypercalcemia associated with some types of cancer. Parathyroid Hormone Receptors Type 1 PTH receptor: PTH and amino- terminal peptides of Type 2 PTH receptor: Binds PTHrP. PTH, but has very low G protein-coupled affinity for PTHrP. Only receptor expressed in a few tissues- its structure and physiologic significance are poorly characterized. Like the type 1 receptor, it is coupled to adenylyl cyclase and ligand binding induces a rise in intracellular concentration of cyclic AMP. Physiologic Effects of Parathyroid Hormone Parathyroid hormone accomplishes its job by stimulating at least three processes: Mobilization of calcium from bone Although the mechanisms remain obscure, a well- documented effect of parathyroid hormone is to stimulate osteoclasts to reabsorb bone mineral, liberating calcium into blood. Physiologic Effects of Parathyroid Hormone Enhancing absorption of calcium from the small intestine: Facilitating calcium absorption from the small intestine would clearly serve to elevate blood levels of calcium. PTH stimulates this process, but indirectly by stimulating production of the active form of vitamin D in the kidney. Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood. Physiologic Effects of Parathyroid Hormone Parathyroid hormone accomplishes its job by stimulating at least three processes: Suppression of calcium loss in urine: In addition to stimulating fluxes of calcium into blood from bone and intestine, PTH puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium. Another effect of PTH on the kidney is to stimulate loss of phosphate ions in urine. Control of Parathyroid Hormone Secretion PTH is released in response to low extracellular concentrations of free calcium. Changes in blood phosphate concentration can be associated with changes in PTH secretion, but this appears to be an indirect effect and phosphate per se is not a significant regulator of this hormone. Control of Parathyroid Hormone Secretion When calcium concentrations fall below the normal range, there is a steep increase in secretion of PTH. Low levels of the hormone are secreted even when blood calcium levels are high. The figure depicts PTH release from cells cultured in vitro in differing concentrations of calcium. The parathyroid cell monitors extracellular free calcium concentration via an integral membrane protein that functions as a calcium-sensing receptor. Extracellular Calcium-Sensing Receptor Maintaining tight control over the concentration of calcium in blood and extracellular fluid is a critical task. It stands to reason that a calcium sensor would evolve as a component of the system responsible for calcium homeostasis. Considering its involvement in modulating so many physiologic processes, calcium itself can be thought of as a type of hormone, and the calcium sensor as its receptor. The DNA sequence encoding the extracellular calcium sensor was originally isolated from bovine parathyroid gland. Since then, corresponding sequences have been isolated from a broad range of species, enabling serious study of this intriguing membrane protein. The calcium-sensing receptor is a member of the G protein-coupled receptor family. Like other family members, it contains 7TMDs and is present in PM. The large (~600 amino acids) extracellular domain is known to be critical to interactions with extracellular calcium. The receptor also has a rather large (~200 amino acids) cytosolic tail. -intracellular domain has kinase phosphorylation sites. The calcium sensor is expressed in a broad range of cells, including parathyroid cells and C cells in the thyroid gland, indicating its involvement in controlling the synthesis and secretion of parathyroid hormone and calcitonin. Functional studies and investigation of animals with mutations in the calcium sensor gene have confirmed that the calcium sensor directly affects secretion of these two hormones. Calcitonin Calcitonin is a hormone involved in calcium and phosphorus metabolism. In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is also synthesized in a wide variety of other tissues. Calcitonin is a 32 aa peptide cleaved from a larger prohormone. It contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring. Calcitonin Calcitonin is a hormone involved in calcium and phosphorus metabolism. Alternative splicing of the calcitonin pre-mRNA can yield a mRNA encoding calcitonin gene- related peptide; that peptide appears to function in the nervous and vascular systems. The calcitonin receptor has been cloned and shown to be a member of the 7TMD, G protein-coupled receptor family. Calcitonin Physiologic Effects of Calcitonin A large and diverse set of effects has been attributed to calcitonin, but in many cases, these were seen in response to pharmacologic doses of the hormone, and their physiologic relevance is suspect. It is clear however, that calcitonin plays a role in calcium and phosphorus metabolism. Calcitonin Physiologic Effects of Calcitonin calcitonin has the ability to decrease blood calcium levels at least in part by effects on two well-studied target organs: Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood. Kidney: Calcium and phosphorus are prevented from being lost in urine by reabsorption in the kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates of their loss in urine. Calcitonin There are species differences in the importance of calcitonin as a factor affecting calcium homeostasis. In fish, rodents and some domestic animals, calcitonin appears to play a significant role in calcium homeostasis. In humans, calcitonin has at best a minor role in regulating blood concentrations of calcium. One interesting piece of evidence to support this statement is that humans with chronically increased (medullary thyroid cancer) or decreased (surgical removal of the thyroid gland) levels of calcitonin in blood usually do not show alterations from normal in serum calcium concentration. Calcitonin Control of Calcitonin Secretion The most prominent factor controlling calcitonin secretion is the extracellular concentration of ionized calcium. Elevated blood calcium levels strongly stimulate calcitonin secretion, and secretion is suppressed when calcium concentration falls below normal. A number of other hormones have been shown to stimulate calcitonin release in certain situations, and nervous controls have also been demonstrated. Calcitonin Disease States A large number of diseases are associated with abnormally increased or decreased levels of calcitonin, but pathologic effects of abnormal calcitonin secretion per se are not generally recognized. Endocrine Control of Calcium and Phosphate Homeostasis It would be very difficult to name a physiologic process that does not depend, in one way or another, on calcium. critical to maintain blood calcium concentrations within a tight normal range. Deviations above or below the normal range frequently lead to serious disease. Endocrine Control of Calcium and Phosphate Homeostasis Hypocalcemia refers to low blood calcium concentration. Clinical signs of this disorder reflect increased neuromuscular excitability and include muscle spasms, tetany and cardiac dysfunction. Tetany -the involuntary contraction of muscle caused by diseases and other conditions that increase the action potential frequency. Endocrine Control of Calcium and Phosphate Homeostasis Tetany Mechanism When the membrane potential is upset, for instance by low levels of ions (such as Ca++) in the blood (hypocalcemia), neurons will depolarize too easily. In the case of hypocalcaemia, calcium ions are drawn away from their association with the voltage-gated sodium channels thus sensitizing them. The upset to membrane potential is therefore caused by an influx of sodium to the cell, not directly by the hypocalcaemia. As a result, too many action potentials are sent to muscles causing spasm. Endocrine Control of Calcium and Phosphate Homeostasis Hypocalcemia refers to low blood calcium concentration. Clinical signs of this disorder reflect increased neuromuscular excitability and include muscle spasms, tetany and cardiac dysfunction. Hypercalcemia indicates a concentration of blood calcium higher than normal. The normal concentration of calcium and phosphate in blood and extracellular fluid is near the saturation point; elevations can lead to diffuse precipitation of calcium phosphate in tissues, leading to widespread organ dysfunction and damage. Preventing hypercalcemia and hypocalcemia is largely the result of robust endocrine control systems. Body Distribution of Calcium and Phosphate 3 major pools of calcium in the body: Intracellular calcium: A large majority of calcium within cells is sequestered in mitochondria and ER. Intracellular free calcium concentrations fluctuate greatly, from roughly 100 nM to greater than 1 uM, due to release from cellular stores or influx from extracellular fluid. These fluctuations are integral to calcium's role in intracellular signaling, enzyme activation and muscle contractions. Body Distribution of Calcium and Phosphate 3 major pools of calcium in the body: Calcium in blood and extracellular fluid: Roughly half of the calcium in blood is bound to proteins. The concentration of ionized calcium in this compartment is normally almost invariant at approximately 1 mM, or 10,000 times the basal concentration of free calcium within cells. Also, the concentration of phosphorus in blood is essentially identical to that of calcium. Body Distribution of Calcium and Phosphate 3 major pools of calcium in the body: Bone calcium: A vast majority of body calcium is in bone. Within bone, 99% of the calcium is tied up in the mineral phase, but the remaining 1% is in a pool that can rapidly exchange with extracellular calcium. Endocrine Control of Calcium and Phosphate Homeostasis Fluxes of Calcium and Phosphate Maintaining constant concentrations of calcium in blood requires frequent adjustments, which can be described as fluxes of calcium between blood and other body compartments. Three organs participate in supplying calcium to blood and removing it from blood when necessary: Endocrine Control of Calcium and Phosphate Homeostasis Three organs participate in supplying calcium to blood and removing it from blood when necessary: The SI is the site where dietary calcium is absorbed. Importantly, efficient absorption of calcium in the SI is dependent on expression of a calcium-binding protein Bone serves as a vast reservoir of calcium. Stimulating net resorption of bone mineral releases calcium and phosphate into blood, and suppressing this effect allows calcium to be deposited in bone. Endocrine Control of Calcium and Phosphate Homeostasis Fluxes of Calcium and Phosphate The kidney is critically important in calcium homeostasis. Under normal blood calcium concentrations, almost all of the calcium that enters glomerular filtrate is reabsorbed from the tubular system back into blood, which preserves blood calcium levels. If tubular reabsorption of calcium decreases, calcium is lost by excretion into urine. Hormonal Control Systems Maintaining normal blood calcium and phosphorus concentrations is managed through the concerted action of three hormones that control fluxes of calcium in and out of blood and extracellular fluid: Hormonal Control Systems PTH serves to increase blood concentrations of calcium. Mechanistically, PTH preserves blood calcium by several major effects: Stimulates production of the biologically-active form of vitamin D within the kidney. Facilitates mobilization of calcium and phosphate from bone. To prevent detrimental increases in phosphate, PTH also has a potent effect on the kidney to eliminate phosphate (phosphaturic effect). Maximizes tubular reabsorption of calcium within the kidney. This activity results in minimal losses of calcium in urine. Hormonal Control Systems Vitamin D acts also function to increase blood concentrations of calcium. It is generated through the activity of PTH within the kidney. Far and away the most important effect of vitamin D is to facilitate absorption of calcium from the small intestine. In concert with PTH, vitamin D also enhances fluxes of calcium out of bone. Calcitonin is a hormone that functions to reduce blood calcium levels. Vitamin D (Cholecalciferol, Calcitriol) Vitamin D is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. More recently, it has become clear that receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism. Structure and Synthesis-Vitamin D The term vitamin D actually refers to a group of steroid molecules. Vitamin D3, also known as cholecalciferol is generated in the skin of animals when light energy is absorbed by a precursor molecule 7-dehydrocholesterol. Structure and Synthesis-Vitamin D Vitamin D is thus not a true vitamin, because individuals with adequate exposure to sunlight do not require dietary supplementation. There are dietary sources of vitamin D, including egg yolk, fish oil and a number of plants. The plant form of vitamin D is called vitamin D2 or ergosterol. However, natural diets typically do not contain adequate quantities of vitamin D, and exposure to sunlight or consumption of foodstuffs purposefully supplemented with vitamin D are necessary to prevent deficiencies. Vitamin D, as either D3 or D2, does not have significant biological activity. Rather, it must be metabolized within the body to the hormonally- active form. This transformation occurs in 2 steps, as depicted in the diagram on the next slide Within the liver, cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25- hydroxylase. Within the kidney, 25-vitamin D serves as a substrate for 1-alpha-hydroxylase, yielding 1,25- dihydroxycholecalciferol, the biologically active form of vitamin D. Each of the forms of vitamin D is hydrophobic and is transported in blood bound to carrier proteins. The major carrier is called, appropriately, vitamin D- binding protein. The half-life of 25-hydroxycholecalciferol is several weeks, while that of 1,25-dihydroxycholecalciferol is only a few hours. Control of Vitamin D Synthesis Hepatic synthesis of 25-hydroxycholecalciferol is only loosely regulated, and blood levels of this molecule largely reflect the amount of amount of vitamin D produced in the skin or ingested. In contrast, the activity of 1-alpha-hydroxylase in the kidney is tightly regulated and serves as the major control point in production of the active hormone. The major inducer of 1- alpha-hydroxylase is PTH: it is also induced by low blood levels of phosphate. The Vitamin D Receptor and Mechanism of Action The active form of vitamin D binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor (RXR), and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription. The vitamin D receptor binds several forms of cholecalciferol. Its affinity for 1,25- dihydroxycholecalciferol is roughly 1000 times that for 25-hydroxycholecalciferol, which explains their relative biological potencies. Physiological Effects of Vitamin D Vitamin D is well known as a hormone involved in mineral metabolism and bone growth. Its most dramatic effect is to facilitate intestinal absorption of calcium, although it also stimulates absorption of phosphate and magnesium ions. Physiological Effects of Vitamin D In the absence of vitamin D, dietary calcium is not absorbed at all efficiently. Vitamin D stimulates the expression of a number of proteins involved in transporting calcium from the lumen of the intestine, across the epithelial cells and into blood. The best-studied of these calcium transporters is calbindin, an intracellular protein that ferries calcium across the intestinal epithelial cell. Physiological Effects of Vitamin D Numerous effects of vitamin D on bone have been demonstrated. As a transcriptional regulator of bone matrix proteins, it induces the expression of osteocalcin and suppresses synthesis of type I collagen. In cell culture, vitamin D stimulates differentiation of osteoclasts. However, studies of humans and animals with vitamin D deficiency or mutations in the vitamin D receptor suggest that these effects are perhaps not of major physiologic importance, and that the crucial effect of vitamin D on bone is to provide the proper balance of calcium and phosphorus to support mineralization. Physiological Effects of Vitamin D Vitamin D receptors are present in most if not all cells in the body. Additionally, experiments using cultured cells have demonstrated that vitamin D has potent effects on the growth and differentiation of many types of cells. Hence, vitamin D has physiologic effects much broader that a role in mineral homeostasis & bone function. Disease States Vitamin D deficiency: The classical manifestations of vitamin D deficiency is rickets, which is seen in children and results in bony deformaties including bowed long bones. Disease States Deficiency in adults leads to the disease osteomalacia. Both rickets and osteomalacia reflect impaired mineralization of newly synthesized bone matrix, and usually result from a combination of inadequate exposure to sunlight and decreased dietary intake of vitamin D. Disease States Vitamin D deficiency or insufficiency occurs in several other situations, which you might predict based on the synthetic pathway Genetic defects in the vitamin D receptor: a number of different mutations have been identified in humans that lead to hereditary vitamin D resistance. Severe liver or kidney disease: this can interfere with generation of the biologically-active form of vitamin D. Disease States Insufficient exposure to sunlight: Elderly people that stay inside and have poor diets often have at least subclinical deficiency. Disease States Ironically, it appears that hypovitaminosis D is very common in some of the most sunny countries in the world - the cause of this problem is the cultural dictate that women be heavily veiled when outside in public. Disease States Sunscreens, especially those with SPF ratings greater than 8, effectively block synthesis of vitamin D in the skin. However, people that use such sunscreens usually live in industrial countries where many foods are supplemented with vitamin D, and vitamin D deficiency is thereby averted by dietary intake. Disease States Vitamin D toxicity: Excessive exposure to sunlight does not lead to overproduction of vitamin D. Vitamin D toxicity is inevitably the result of overdosing on vitamin D supplements. Don't do this! Ingestion of milligram quantities of vitamin D over periods of weeks of months can be severely toxic to humans and animals. In fact, baits laced with vitamin D are used very effectively as rodenticides. Disease States Both increased and decreased secretion of PTH are recognized as causes of serious disease in man and animals. Excessive secretion of parathyroid hormone is seen in two forms: Primary hyperparathyroidism Is the result of parathyroid gland disease, most commonly due to a parathyroid tumor (adenoma) which secretes the hormone without proper regulation. Common manifestations of this disorder are chronic elevations of blood calcium concentration (hypercalcemia), kidney stones and decalcification of bone. hypercalcemia is what usually signals the doctor that something may be wrong with the parathyroid glands. In 85% of people with this disorder, a benign tumor (adenoma) has formed on one of the parathyroid glands, causing it to become overactive. In most other cases, the excess hormone comes from two or more enlarged parathyroid glands, a condition called hyperplasia. Very rarely, hyperparathyroidism is caused by cancer of a parathyroid gland. This excess PTH triggers the release of too much calcium into the bloodstream. The bones may lose calcium, and too much calcium may be absorbed from food. The levels of calcium may increase in the urine, causing kidney stones. PTH also acts to lower blood phosphorous levels by increasing excretion of phosphorus in the urine. Why Are Calcium and Phosphorous So Important? Calcium is essential for good health. It plays an important role in bone and tooth development and in maintaining bone strength. It is also important in nerve transmission and muscle contraction. Phosphorous is found in every body tissue. Combined with calcium, it gives strength and rigidity to your bones and teeth. What Causes Hyperparathyroidism? In most cases doctors don't know the cause. The vast majority of cases occur in people with no family history of the disorder. Only about 3-5 % of cases can be linked to an inherited problem. Familial endocrine neoplasia type I is one rare inherited syndrome that affects the parathyroids as well as the pancreas and the pituitary gland. Another rare genetic disorder, familial hypocalciuric hypercalcemia, is sometimes confused with typical hyperparathyroidism. How Common Is Hyperparathyroidism? In the U.S., about 100,000 people develop the disorder each year. Women outnumber men by 2 to 1, and risk increases with age. In women 60 years and older, 2 out of 1,000 will get hyperparathyroidism. What Are the Symptoms of Hyperparathyroidism? may have severe symptoms, subtle ones, or none at all. Increasingly, routine blood tests that screen for a wide range of conditions including high calcium levels are alerting doctors to people who, though symptom-free, have mild forms of the disorder. What Are the Symptoms of Hyperparathyroidism? When symptoms do appear, they are often mild and nonspecific, such as a feeling of weakness and fatigue, depression, or aches and pains. With more severe disease, a person may have a loss of appetite, nausea, vomiting, constipation, confusion or impaired thinking and memory, and increased thirst and urination. Patients may have thinning of the bones without symptoms, but with risk of fractures. Increased calcium and phosphorous excretion in the urine may cause kidney stones. Patients with hyperparathyroidism may be more likely to develop peptic ulcers, high blood pressure, and pancreatitis. How Is Hyperparathyroidism Diagnosed? Hyperparathyroidism is diagnosed when tests show that blood levels of calcium as well as PTH are too high. Other diseases can cause high blood calcium levels, but only in hyperparathyroidism is the elevated calcium the result of too much PTH. A blood test that accurately measures the amount of PTH has simplified the diagnosis of hyperparathyroidism. How Is Hyperparathyroidism Diagnosed? Once the diagnosis is established, other tests may be done to assess complications. Because high PTH levels can cause bones to weaken from calcium loss, a measurement of bone density may be done to assess bone loss and the risk of fractures. Abdominal radiographs may reveal the presence of kidney stones and a 24-hour urine collection may provide information on kidney damage and the risk of stone formation. How Is Hyperparathyroidism Treated? Surgery to remove the enlarged gland(s) is the only treatment for the disorder and cures it in 95 % of cases. However, some patients who have mild disease may not need immediate treatment, according to a panel of experts convened by the National Institutes of Health in 1990. Patients who are symptom-free, whose blood calcium is only slightly elevated, and whose kidneys and bones are normal, may wish to talk to their doctor about long- term monitoring. How Is Hyperparathyroidism Treated? In the panel's recommendation, monitoring would consist of clinical evaluation and measurement of calcium levels and kidney function every 6 months, annual abdominal x-ray, and bone mass measurement after 1 to 2 years. If the disease shows no signs of worsening after 1 to 3 years, the interval between exams may be lengthened. If the patient and doctor choose long-term followup, the patient should try to drink lots of water, and get plenty of exercise. Immobilization and gastrointestinal illness with vomiting or diarrhea can cause calcium levels to rise, and if these conditions develop, patients with hyperparathyroidism should seek medical attention. Are There Any Complications Associated With Parathyroid Surgery? Surgery for hyperparathyroidism is highly successful with a low complication rate when performed by surgeons experienced with this condition. About 1% of patients undergoing surgery have damage to the nerves controlling the vocal cords, which can affect speech. 1-5% of patients develop chronic low calcium levels, which may require treatment with calcium and/or vitamin D. The complication rate is slightly higher for hyperplasia than it is for adenoma since more extensive surgery is needed. Are Parathyroid Imaging Tests Needed Before Surgery? NOPE The NIH panel recommended against the use of expensive imaging tests to locate benign tumors before initial surgery. Research shows that such tests do not improve the success rate of surgery, which is about 95 % when performed by experienced surgeons. Localization tests are useful in patients having a second operation for recurrent or persistent hyperparathyroidism. Secondary hyperparathyroidism is the situation where disease outside of the parathyroid gland leads to excessive secretion of parathyroid hormone. A common cause of this disorder is kidney disease - if the kidneys are unable to reabsorb calcium, blood calcium levels will fall, stimulating continual secretion of parathyroid hormone to maintain normal calcium levels in blood. Secondary hyperparathyroidism can also result from inadequate nutrition - for example, diets that are deficient in calcium or vitamin D, or which contain excessive phosphorus (e.g. all meat diets for carnivores). A prominent effect of secondary hyperparathyroidism is decalcification of bone, leading to pathologic fractures or "rubber bones". There is no doubt that chronic secretion or continuous infusion of PTH leads to decalcification of bone and loss of bone mass. However, in certain situations, treatment with PTH can actually stimulate an increase in bone mass and bone strength. This seemingly paradoxical effect occurs when the hormone is administered in pulses (e.g. by once daily injection), and such treatment appears to be an effective therapy for diseases such as osteoporosis. Inadequate production of parathyroid hormone – hypoparathyroidism - typically results in decreased concentrations of calcium and increased concentrations of phosphorus in blood. Common causes of this disorder include surgical removal of the parathyroid glands and disease processes that lead to destruction of parathyroid glands. The resulting hypocalcemia often leads to tetany and convulsions, and can be acutely life-threatening. Treatment focuses on restoring normal blood calcium concentrations by calcium infusions, oral calcium supplements and vitamin D therapy. Parathyroid Hormone-Related Protein Parathyroid hormone-related protein (PTHrP) is actually a family of protein hormones produced by most if not all tissues in the body. A segment of PTHrP is closely related to PTH, hence its name, but these peptides have a much broader spectrum of effects. PTH and some of the PTHrP peptides bind to the same receptor, but PTHrP peptides also bind to several other receptors. Parathyroid Hormone-Related Protein . PTHRP was discovered as a protein secreted by certain tumors that caused hypercalcemia (elevated blood calcium levels) in affected patients. It was soon shown that the uncontrolled secretion of PTHRP by many tumor cells induces hypercalcemia by stimulating resorption of calcium from bone and suppressing calcium loss in urine, similar to what is seen with hyperparathyroidism. However, it quickly become apparent that PTHRP had many activities not seen with PTH. Hormone Structures, Receptors and Sources PTHrP is encoded by a single gene that is highly conserved among species. It should probably be described as a polyhormone, because a family of peptide hormones are generated by alternative splicing of the primary transcript and through use of alternative post-translational cleavage sites. To make matters even more complex, some cells appear to use alternative translational initiation codons to produce forms of the protein that are targeted either for secretion or nuclear localization. The figure below shows one of the characterized processing patterns of the PTHrP preprohormone, in this case yielding 3 bioactive peptides. Parathyroid Hormone-Related Protein The diverse activities of PTHrP result not only from processing of the precursor into multiple hormones, but from use of multiple receptors. It is clear that amino- terminal peptides of PTHrP share a receptor with PTH, but they also bind to a type of receptor in some tissues that does not bind PTH. Moreover, it is almost certain that the midregion and osteostatin peptides bind other, unique receptors. In addition to the secreted forms, there is considerable evidence that a form of PTHrP is generated in some cells that is not secreted and, via nuclear targeting sequences, is translocated to the nucleus, where it affects nuclear function. Parathyroid Hormone-Related Protein Moreover, it is almost certain that the midregion and osteostatin peptides bind other, unique receptors. In addition to the secreted forms, there is considerable evidence that a form of PTHrP is generated in some cells that is not secreted and, via nuclear targeting sequences, is translocated to the nucleus, where it affects nuclear function. The consequences of this "intracrine" mode of action are not yet well characterized, but may modulate such important activities as programmed cell death. Parathyroid Hormone-Related Protein PTHrP is secreted from a large and diverse set of cells, and during both fetal and postnatal life. Among tissues known to secrete this hormone are several types of epithelium, mesenchyme, vascular smooth muscle and central nervous system. Although PTHrP is found in serum, a majority of its activity appears to reflect paracrine signaling. Physiologic Effects of Parathyroid Hormone- Related Protein One thing to recognize about PTHrP is that its name is inadequate to describe its activities. Like PTH, some of the effects of PTHrP result from its effects on transepithelial fluxes of calcium, but many of its actions have nothing to do with calcium homeostasis. Most prominently, PTHrP peptides exert significant control over the proliferation, differentiation and death of many cell types. They also play a major role in development of several tissues and organs. Physiologic Effects of Parathyroid Hormone-Related Protein . Much of our understanding of the biologic effects of PTHrP comes from experiments with transgenic mice. Mice with targeted deletions in the PTHrP gene (knockout mice), mice that overexpress PTHrP in specific tissues (transgenic mice), and crosses between knockout and transgenic mice have been critical in delineating many effects of this hormone. Humans with mutations in the PTHrP gene or the parathyroid receptor have also played a role in confirming the activity of PTHrP. Some of the physiologic effects of PTHrP garnered from these studies are indicated on next few slides Physiologic Effects of Parathyroid Hormone-Related Protein Cartilage and Bone Development: Mice null for PTHrP gene die at birth, if not earlier. A developmental defect in proliferation and differentiation of cartilage. These and other types of studies indicate that PTHrP stimulates the proliferation of chondrocytes and suppresses their terminal differentiation. These effects of PTHrP appear due to interaction of the PTH-like peptide with the PTH receptor. Physiologic Effects of Parathyroid Hormone-Related Protein . Mammary Development and Lactation: The mammary glands of female mice with homozygous inactivation of the PTHrP gene fail to develop, except for the earliest stages. Development of the mammary gland depends upon a complex interaction between epithelial and mesenchymal cells that apparently requires PTHrP. In normal animals, mammary epithelial cells secrete large amounts of PTHrP, which suggests a role of this hormone in adapting maternal metabolism to the calcium demands of lactation. Placental Transfer of Calcium: The "midregion" peptide of PTHrP (see above) has been shown to control the normal maternal-to- fetal pumping of calcium across the placenta. In the absence of fetal PTHrP, this gradient is not established. Physiologic Effects of Parathyroid Hormone-Related Protein Smooth Muscle Functioning: PTHrP is secreted from smooth muscle usually in response to stretching. It acts to relax smooth muscle, thereby serving, among other things, as a vasodilating hormone. Transgenic mice that express PTHrP in vascular smooth muscle manifest hypotension. PTHrP may also have effects on contraction of muscle in the bladder, uterus and heart. Physiologic Effects of Parathyroid Hormone-Related Protein Other Effects: PTHrP is highly expressed in skin. Transgenic mice that overexpress PTHrP in skin show alopecia, and treatment of mice with a PTHrP antagonist leads to increased numbers of hair follicles and a shaggy appearance. Another interesting defect in PTHrP-null mice is that teeth develop normally, they fail to erupt. Finally, both PTHrP and its receptors are widely expressed in the CNS, and appear to influence neuronal survival by several mechanisms. It should be clear from the above examples that PTHrP hormones have profound effects on a large number of physiologic processes. Ongoing research on this polyhormone is certain to reveal additional effects in this already complex system.
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