New Endocrinology

Where do hormones come from
Natalia Lvovna Reznik, PhD, "Chemistry and Life" No. 1-2011
The article is published on the website "Elements"Dental hormone

What hormones are, everyone more or less represents.

Until recently, it was assumed that they are synthesized by endocrine glands or specialized endocrine cells scattered throughout the body and combined into a diffuse endocrine system. The cells of the diffuse endocrine system develop from the same germ leaf as the nervous ones, therefore they are called neuroendocrine. They have been found everywhere: in the thyroid gland, adrenal medulla, hypothalamus, epiphysis, placenta, pancreas and gastrointestinal tract. And recently they were found in the pulp of the tooth, and it turned out that the number of neuroendocrine cells in it varies depending on the health of the teeth.

The honor of this discovery belongs to Alexander Vladimirovich Moskovsky, associate professor of the Department of Orthopedic Dentistry of the Medical Institute at the I. N. Ulyanov Chuvash State University. Neuroendocrine cells are characterized by characteristic proteins, and they can be detected by immunological methods. That's how A.V. Moskovsky discovered them. (This study was published in No. 9 of the Bulletin of Experimental Biology and Medicine for 2007.)

Pulp is the soft core of the tooth, in which nerves and blood vessels are located. It was extracted from the teeth and sections were prepared, on which specific proteins of neuroendocrine cells were then searched. We did it in three stages. First, the prepared sections were treated with antibodies to the desired proteins (antigens). Antibodies consist of two parts: specific and non-specific. After binding to antigens, they remain on the slice with a non-specific part upwards. The slice is treated with antibodies to this non-specific part, which are labeled with biotin. Then this "sandwich" with biotin is treated with special reagents on top, and the location of the source protein appears as a reddish speck.

Neuroendocrine cells differ from connective tissue cells in larger sizes, irregular shape and the presence of reddish-brown lumps (colored proteins) in the cytoplasm, often covering the nucleus.

There are few neuroendocrine cells in a healthy pulp, but their number increases with caries. If the tooth is not treated, the disease progresses, and neuroendocrine cells become more and more, and they accumulate around the lesion. The peak of their number falls on caries so neglected that the tissues around the tooth become inflamed, that is, periodontitis begins.

Patients who prefer to suffer at home for a long time than to go to the doctor once develop inflammation of the pulp and periodontal. At this stage, the number of neuroendocrine cells decreases (although there are still more of them than in a healthy pulp) — they are displaced by inflammatory cells (leukocytes and macrophages). Their number also decreases with chronic pulpitis, but with this disease there are few cells in the pulp at all, they are replaced by sclerotic strands.

According to A.V. Moskovsky, neuroendocrine cells in caries and pulpitis regulate microcirculation and metabolism processes in the focus of inflammation. Since there are also more nerve fibers in caries and pulpitis, the endocrine and nervous systems also work together in this matter.

Hormones everywhere?In recent years, scientists have found out that hormone production is not the prerogative of specialized endocrine cells and glands.

This is also done by other cells, which have many other tasks. Their list is growing year by year. It contains various blood cells (lymphocytes, eosinophilic leukocytes, monocytes and platelets), macrophages crawling outside blood vessels, endothelial cells (lining of blood vessels), thymus epithelial cells, chondrocytes (from cartilage tissue), cells of amniotic fluid and placental trophoblast (the part of the placenta that grows into the uterus) and endometrium (this is from the uterus itself), Leydig cells of the testes, some retinal cells and Merkel cells located in the skin around the hair and in the epithelium of the subcutaneous bed, muscle cells. The list of hormones synthesized by them is also quite long.

Take, for example, mammalian lymphocytes. In addition to their production of antibodies, they synthesize melatonin, prolactin, ACTH (adrenocorticotropic hormone) and somatotropic hormone. The "homeland" of melatonin is traditionally considered to be the epiphysis, a gland located deep in the human brain. It is also synthesized by cells of the diffuse neuroendocrine system. The spectrum of action of melatonin is wide: it regulates biorhythms (which is especially famous), differentiation and division of cells, suppresses the growth of some tumors and stimulates the production of interferon. Prolactin, which causes lactation, is produced by the anterior pituitary gland, but in lymphocytes it acts as a cell growth factor. ACTH, which is also synthesized in the anterior pituitary gland, stimulates the synthesis of steroid hormones of the adrenal cortex, and regulates the formation of antibodies in lymphocytes.

And the cells of the thymus, the organ in which T-lymphocytes are formed, synthesize luteinizing hormone (pituitary hormone that causes the synthesis of testosterone in the testes and estrogen in the ovaries). In the thymus, it probably stimulates cell division.

The synthesis of hormones in lymphocytes and thymus cells is considered by many experts as proof of the existence of a connection between the endocrine and immune systems. But it is also a very illustrative illustration of the current state of endocrinology: it cannot be said that a certain hormone is synthesized there and does something. There can be many places of its synthesis, functions too, and often they depend on the place of hormone formation.

The endocrine layerSometimes a cluster of nonspecific hormone-producing cells forms a full-fledged endocrine organ, and a rather big one, such as, for example, adipose tissue.

However, its dimensions are variable, and depending on them, the spectrum of "fat" hormones and their activity change.

Fat, which causes so much trouble to modern man, is actually a most valuable evolutionary acquisition.

In the 1960s, the American geneticist James Neal formulated the hypothesis of "lean genes". According to this hypothesis, periods of prolonged starvation are characteristic of the early history of mankind, and not only for the early one. Those who survived in the intervals between the hungry years managed to eat off, so that later there was something to lose weight. Therefore, evolution selected alleles that contributed to rapid weight gain, and also inclined a person to low mobility — sedentary, you can't shake fat. (There are already several hundred known genes that influence the style of behavior and the development of obesity.) But life has changed, and these internal reserves are no longer for the future, but for the disease. Excess fat causes a serious ailment — metabolic syndrome: a combination of obesity, insulin resistance, high blood pressure and chronic inflammation. A patient with metabolic syndrome will not have long to wait for cardiovascular diseases, type II diabetes and many other ailments. And all this is the result of the action of adipose tissue as an endocrine organ.

The main cells of adipose tissue, adipocytes, are not at all similar to secretory cells. However, they not only store fat, but also secrete hormones. The main one, adiponectin, prevents the development of atherosclerosis and general inflammatory processes. It affects the passage of the signal from the insulin receptor and thereby prevents the occurrence of insulin resistance. Fatty acids in muscle and liver cells are oxidized faster under its action, there are fewer reactive oxygen species, and diabetes, if it already exists, proceeds more easily. Moreover, adiponectin regulates the work of the adipocytes themselves.

It would seem that adiponectin is indispensable for obesity and can prevent the development of metabolic syndrome. But, alas, the more adipose tissue grows, the less hormone it produces. Adiponectin is present in the blood in the form of trimers and hexamers. With obesity, there are more trimers and fewer hexamers, although hexamers interact much better with cellular receptors. And the very number of receptors decreases with the growth of adipose tissue. So the hormone does not just become less, it also acts weaker, which, in turn, contributes to the development of obesity. It turns out a vicious circle. But it can be broken — lose 12 kilograms, no less, then the number of receptors returns to normal.

Another wonderful hormone of adipose tissue is leptin. Like adipokinetin, it is synthesized by adipocytes. Leptin is known for suppressing appetite and accelerating the breakdown of fatty acids. He achieves this effect by interacting with certain neurons of the hypothalamus, and then the hypothalamus itself disposes. With excess body weight, leptin production increases significantly, and the neurons of the hypothalamus reduce sensitivity to it, and the hormone wanders through the blood unbound. Therefore, although the level of leptin in the serum of obese patients is increased, people do not lose weight, because the hypothalamus does not perceive its signals. However, there are receptors for leptin in other tissues, their sensitivity to the hormone remains at the same level, and they readily respond to its signals. And leptin, by the way, activates the sympathetic department of the peripheral nervous system and increases blood pressure, stimulates inflammation and promotes the formation of blood clots, in other words, contributes to the development of hypertension and inflammation inherent in the metabolic syndrome.

The development of inflammation and insulin resistance is also caused by another hormone of adipocytes, resistin. Resistin is an insulin antagonist, under its action, heart muscle cells reduce glucose intake and accumulate intracellular fats. And the adipocytes themselves, under the influence of resistin, synthesize much more inflammatory factors: chemotactic protein 1 for macrophages, interleukin-6 and tumor necrosis factor-b (MCP-1, IL-6 and TNF-b). The more resistin in the serum, the higher the systolic pressure, the wider the waist, the greater the risk of developing cardiovascular diseases.

In fairness, it should be noted that the growing adipose tissue seeks to correct the harm caused by its hormones. To this end, the adipocytes of obese patients produce two more hormones in excess: visfatin and apelin. However, their synthesis occurs in other organs, including skeletal muscles and the liver. In principle, these hormones resist the development of metabolic syndrome. Visfatin acts like insulin (binds to the insulin receptor) and lowers blood glucose levels, and also activates the synthesis of adiponectin in a very complex way. But of course this hormone cannot be called useful, since visfatin stimulates the synthesis of inflammatory signals. Apelin suppresses insulin secretion by binding to pancreatic beta cell receptors, lowers blood pressure, and stimulates contraction of heart muscle cells. With a decrease in the mass of adipose tissue, its content in the blood decreases. Unfortunately, apelin and visfatin cannot resist the action of other adipocyte hormones.

The effect of adipose tissue hormonesHormonal activity of adipose tissue explains why overweight leads to such serious consequences.

However, scientists have recently discovered a larger endocrine organ in the mammalian body. It turns out that our skeleton produces at least two hormones. One regulates the processes of bone mineralization, the other regulates the sensitivity of cells to insulin.

The bone takes care of itselfReaders of Chemistry and Life know, of course, that the bone is alive.

Osteoblasts build it. These cells synthesize and secrete a large number of proteins, mainly collagen, osteocalcin and osteopontin, which create an organic bone matrix, which is then mineralized. During mineralization, calcium ions bind to inorganic phosphates to form hydroxyapatite [Ca ₁₀(PO)₄(OH)₂]. Surrounding themselves with a mineralized organic matrix, osteoblasts turn into osteocytes — mature, multi-process spindle-shaped cells with a large rounded nucleus and a small number of organelles. Osteocytes do not come into contact with the calcified matrix, there is a gap about 0.1 microns wide between them and the walls of their "caves", and the walls themselves are lined with a thin, 1-2 microns, layer of non-mineralized tissue. Osteocytes are connected to each other by long processes passing through special tubules. Tissue fluid that feeds the cells circulates through the same tubules and cavities around the osteocytes.

Bone mineralization proceeds normally under several conditions. First of all, a certain concentration of calcium and phosphorus in the blood is necessary. These elements come with food through the intestines, and come out with urine. Therefore, the kidneys, filtering urine, must retain calcium and phosphorus ions in the body (this is called reabsorption).

Proper absorption of calcium and phosphorus in the intestine is provided by the active form of vitamin D (calcitriol). It also affects the synthetic activity of osteoblasts. Vitamin D is converted into calcitriol by the action of the enzyme 1b-hydroxylase, which is synthesized mainly in the kidneys. Another factor affecting the level of calcium and phosphorus in the blood and the activity of osteoblasts is parathyroid hormone (PTH), a product of the parathyroid glands. PTH interacts with bone, kidney and intestinal tissues and weakens reabsorption.

But recently, scientists have discovered another factor regulating bone mineralization — FGF23 protein, fibroblast growth factor 23. (A great contribution to these works was made by employees of the pharmaceutical research laboratory of the Kirin Brewing Company and the Department of Nephrology and Endocrinology of the University of Tokyo under the leadership of Takeyoshi Yamashita. FGF23 synthesis occurs in osteocytes, and it acts on the kidneys, controlling the level of inorganic phosphates and calcitriol.

As Japanese scientists have found out, the FGF23 gene (hereafter the genes, unlike their proteins, are indicated in italics) is responsible for two serious diseases: autosomal dominant hypophosphatemic rickets and osteomalacia. To put it simply, rickets is a disturbed mineralization of growing children's bones. And the word "hypophosphatemic" means that the disease is caused by a lack of phosphates in the body. Osteomalacia is the demineralization (softening) of bone in adults caused by a lack of vitamin D. Patients suffering from these ailments have elevated levels of FGF23 protein. Sometimes osteomalacia occurs as a result of the development of a tumor, and not at all bone. FGF23 expression is also increased in the cells of such tumors.

In all patients with FGF23 hyperproduction, the phosphorus content in the blood is reduced, and renal reabsorption is weakened. If the described processes were under the control of PTH, then a violation of phosphorus metabolism would entail increased calcitriol formation. But this is not happening. With osteomalacia of both types, the concentration of calcitriol in the serum remains low. Consequently, FGF23 plays the first fiddle in the regulation of phosphorus metabolism in these diseases, not PTH, but FGF23. As scientists have found out, this enzyme suppresses the synthesis of 1b-hydroxylase in the kidneys, which is why there is a shortage of the active form of vitamin D.

With a lack of FGF23, the picture is reversed: there is an excess of phosphorus in the blood, calcitriol too. A similar situation occurs in mutant mice with elevated protein levels. And in rodents with the missing FGF23 gene, the opposite is true: hyperphosphatization, increased renal reabsorption of phosphates, high calcitriol levels and increased expression of 1b-hydroxylase. As a result, the researchers concluded that FGF23 regulates phosphate metabolism and vitamin D metabolism, and this regulation pathway is different from the previously known pathway involving PTH.

Scientists are now understanding the mechanisms of action of FGF23. It is known that it reduces the expression of proteins responsible for the absorption of phosphates in the renal tubules, as well as the expression of 1b-hydroxylase. Since FGF23 is synthesized in osteocytes, and acts on kidney cells, getting there through the blood, this protein can be called a classic hormone, although no one would dare to call the bone an endocrine gland.

Skeletal hormonesThe level of the hormone depends on the content of phosphate ions in the blood, as well as on mutations in some genes that also affect mineral metabolism (FGF23 is not the only gene with such a function), and on mutations in the gene itself.

This protein, like any other, is in the blood for a certain time, and then it is broken down by special enzymes. But if, as a result of mutation, the hormone becomes resistant to cleavage, it will become too much. And there is also the GALNT3 gene, the product of which cleaves the FGF23 protein. A mutation in this gene causes increased cleavage of the hormone, and at a normal level of synthesis, the patient lacks FGF23 with all the ensuing consequences. There is a protein called KLOTHO, which is necessary for the hormone to interact with the receptor. And somehow FGF23 interacts with PTH, of course. Researchers suggest that it suppresses the synthesis of parathyroid hormone, although they are not completely sure about this. But scientists continue to work and soon, apparently, they will sort out all the actions and interactions of FGF23 to the last bone. We'll wait.

Skeleton and diabetesOf course, proper bone mineralization is impossible without maintaining normal levels of calcium and phosphates in the blood serum.

Therefore, it is quite understandable that the bone "personally" controls these processes. But what does she care about the sensitivity of cells to insulin? However, in 2007, researchers from Columbia University (New York) led by Gerard Karsenty discovered, to the great surprise of the scientific community, that osteocalcin affects the sensitivity of cells to insulin. This, as we remember, is one of the key proteins of the bone matrix, the second most important after collagen, and osteoblasts synthesize it. Immediately after synthesis, a special enzyme carboxylates three residues of glutamic acid osteocalcin, that is, introduces carboxyl groups into them. It is in this form that osteocalcin is included in the bone. But some of the protein molecules remain uncarboxylated. Such osteocalcin is designated uOCN, and it has hormonal activity. The process of osteocalcin carboxylation enhances the osteotesticular protein tyrosine phosphatase (OST-PTP), thus reducing the activity of the hormone uOCN.

It began with the fact that American scientists created a line of "non-osteocalcin" mice. The synthesis of the bone matrix in such animals took place at a higher rate than in ordinary animals, so the bones turned out to be more massive, but they performed their functions well. In the same mice, the researchers found hyperglycemia, low insulin levels, a small number and decreased activity of insulin-producing beta cells of the pancreas and an increased content of visceral fat. (Fat can be subcutaneous and visceral, deposited in the abdominal cavity. The amount of visceral fat depends mainly on nutrition, not on the genotype.) But in mice defective by the OST-PTP gene, that is, with excessive uOCN activity, the clinical picture is reversed: too many beta cells and insulin, hypersensitivity of cells to insulin, hypoglycemia, almost no fat. After uOCN injections, the number of beta cells, the activity of insulin synthesis and sensitivity to it increase in normal mice. Glucose levels are returning to normal. So uOCN is a hormone that is synthesized in osteoblasts, acts on pancreatic cells and muscle cells. And it affects insulin production and sensitivity to it, respectively.

All this was installed on mice, but what about humans? According to a few clinical studies, the level of osteocalcin is positively associated with insulin sensitivity, and it is significantly lower in the blood of diabetics than in people who do not suffer from this disease. However, in these studies, doctors did not distinguish between carboxylated and non-carboxylated osteocalcin. The role of these forms of protein in the human body has yet to be understood.

But what is the role of the skeleton, it turns out! And we thought it was a support for muscles.

FGF23 and osteocalcin are classic hormones. They are synthesized in one organ, and affect others. However, their example shows that hormone synthesis is not always a specific function of selected cells. It is rather general biological and is inherent in any living cell, regardless of its main role in the body.

Not only has the line between endocrine and non-endocrine cells been erased, the very concept of "hormone" is becoming more and more vague. For example, adrenaline, dopamine and serotonin are certainly hormones, but they are also neurotransmitters, because they act both through the blood and through the synapse. And adiponectin has not only an endocrine effect, but also a paracrine effect, that is, it acts not only through blood to distant organs, but also through tissue fluid to neighboring adipose tissue cells. So the subject of endocrinology is changing before our eyes.

Portal "Eternal youth" http://vechnayamolodost.ru14.03.2011