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Blood acidity and bones


By consuming acidic foods, could one cause their blood to become acidic and therefore cause an acid+base reaction between their blood and bone?

I ask this because i recently discovered bone is a base, as its chemical formula is approximated as Ca10(PO4)6(OH)2 where the (OH)2 suggests bone is basic and thus prone to a neutralisation reaction with acidic blood. If so, what salt would be produced?


Short Answer: As the comments mention, this is a hot topic for pseudoscientists to use as a selling point for their supplements. There is limited evidence that dietary acid intake significantly alters bone resorption, especially in the setting of normal renal function. This paper should answer all of your questions (emphasis mine):

Frassetto, Banerjee, Powe, Sebastian. Acid Balance, Dietary Acid Load, and Bone Effects-A Controversial Subject. Nutrients. 2018. 10(4),517.

Abstract: Modern Western diets, with higher contents of animal compared to fruits and vegetable products, have a greater content of acid precursors vs. base precursors, which results in a net acid load to the body. To prevent inexorable accumulation of acid in the body and progressively increasing degrees of metabolic acidosis, the body has multiple systems to buffer and titrate acid, including bone which contains large quantities of alkaline salts of calcium. Both in vitro and in vivo studies in animals and humans suggest that bone base helps neutralize part of the dietary net acid load. This raises the question of whether decades of eating a high acid diet might contribute to the loss of bone mass in osteoporosis. If this idea is true, then additional alkali ingestion in the form of net base-producing foods or alkalinizing salts could potentially prevent this acid-related loss of bone. Presently, data exists that support both the proponents as well as the opponents of this hypothesis. Recent literature reviews have tended to support either one side or the other. Assuming that the data cited by both sides is correct, we suggest a way to reconcile the discordant findings. This overview will first discuss dietary acids and bases and the idea of changes in acid balance with increasing age, then review the evidence for and against the usefulness of alkali therapy as a treatment for osteoporosis, and finally suggest a way of reconciling these two opposing points of view.

This paper is open-access and I recommend you read it, but the conclusions summarize their findings nicely:

7. Synthesis

We suggest the way to put all of this information together is to agree… that bone alone cannot buffer the positive acid balance that one can calculate from measures of acid production and acid excretion. In addition, endogenous acid production goes up and down in an attempt to maintain systemic blood pH…

Diets high in acid precursors add to the body's acid burden. For the majority of people eating typical western diets with acid loads of ≤1 mmol/kg, whose renal function and acid excretory ability is normal, dietary acid loads would not be a readily detectable factor in altering bone mineral density leading to the development of osteoporosis. Other factors such as age, gender, race, and immobility are quantitatively more major factors in determining bone mass and bone breakdown.

However, body retention of only 1 or 2 mEq of acid each day, barely detectable by current measurement techniques, buffered by muscle and kidney and titrated by skeletal base over decades, could potentially result in major depletion of bone mineral. Thus, we suggest that those older subjects with diminished renal function, decreased renal acid excretory ability, and lower buffering capacity due to lower muscle and/or bone mass, whose diets contain high net acid loads could potentially benefit the most from alkali therapies.


Long Answer: Although there's a wealth of pseudoscience on the internet relating to acidemia and bone composition, there is some truth to the idea that bone can be affected by pH. An excellent model to explore this concept is chronic kidney disease, as impaired renal function causes decreased H+ secretion, which results in a chronic metabolic acidosis:

Kopple, Kalantar-Zadeh, Mehrotra. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney International. 2005. 67(95),S21-27.

Metabolic Acidosis

Severe chronic metabolic acidosis (i.e., the presence of excess hydrogen ions in blood) has two well-recognized major systemic consequences. First, metabolic acidosis, or acidemia, induces increased protein catabolism, decreased protein synthesis, and negative nitrogen and total body protein balance, which improve upon bicarbonate supplementation. Second, metabolic acidosis causes physicochemical dissolution of bone and cell-mediated bone resorption (inhibition of osteoblast and stimulation of osteoclast function).

Metabolic Acidosis and Bone Disease

Metabolic acidosis exerts multiple effects on bone. It causes the physicochemical dissolution of bone and cell-mediated bone resorption through the inhibition of osteoblast activity and stimulation of osteoclast function. These events are associated with a loss of calcium and phosphorus from the bone. Metabolic acidosis stimulates osteoblasts to release prostaglandins. This stimulates osteoclast function and inhibits osteoblast activity. Glucocorticoids can inhibit the production of prostaglandins by osteoblasts.

Metabolic acidosis is also associated with a decrease in the content of bone bicarbonate. Additionally, bicarbonate supplementation in postmenopausal women is associated with decreases in urinary calcium, phosphorus, and increased osteocalcin levels, indicating a beneficial effect. Figure 4 shows the mechanisms relating metabolic acidosis with bone disease3. These observations suggest that uncorrected metabolic acidosis has adverse consequences on bone anatomy and physiology.

Figure 4. The various mechanisms by which metabolic acidosis may contribute to bone disease. (From3).

From here, your questions can be answered:

Q: By consuming acidic foods, could one cause their blood to become acidic and therefore cause an acid+base reaction between their blood and bone?

A: Maybe. It is possible to induce a metabolic acidosis with diet:

Adeva, Souto. Diet-induced metabolic acidosis. Clinical Nutrition. 2011. 30(4),416-21.

The modern Western-type diet is deficient in fruits and vegetables and contains excessive animal products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements compensating mechanisms aimed to restore the acid-base balance, such as the removal of the non-metabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and phosphate wasting.

And there is existing research on short-term effects of altered diet on blood and urine pH and composition, but the clinical relevance of these values is indeterminate:

Buclin, Cosma, Appenzeller, Jacquet, Décosterd, Biollaz, Burckhardt. Diet Acids and Alkalis Influence Calcium Retention in Bone. Osteoporosis International. 2001. 12(6),493-99.

The urine-acidifying properties of food constituents depend on their content of non-oxidizable acids or precursors. Acidifying constituents such as animal proteins may negatively affect calcium metabolism and accelerate bone resorption, thus representing an aggravating factor for osteoporosis… acid-forming diet increased urinary calcium excretion by 74% when compared with the base-forming diet (p50.0001), both at baseline and after the oral calcium load, and C-telopeptide excretion by 19% (p=0.01), suggesting a skeletal origin for the excess calcium output. This observation confirms that renally excreted acids derived from food influence calcium metabolism, and that alkalizing nutrients inhibit bone resorption. Further studies are needed to determine the clinical impact of dietary counseling for avoiding diet acids as a preventive measure against osteoporosis.

But best recent evidence does not support the idea that significant changes in bone composition could be induced by diet alone (see my "Short Answer" above).

Q:… what salt would be produced?

There are many metabolic acids, but for simplicity, we'll consider H+. Bone bases are stored as alkaline salts (e.g. calcium carbonate, CaCO3, which is really Ca2+ and CO32-). So, if H+ comes into contact with calcium carbonate, you'll make carbonic acid (with H+ displacing Ca2+ to produce H2CO3 - you excrete the Ca2+, resulting in the hypercalcuria described above). Through the bicarbonate buffer system, that H2CO3 will be converted into carbon dioxide and water, which you excrete from your body via respiration.


14.2: Introduction to the Skeletal System

  • Contributed by Suzanne Wakim & Mandeep Grewal
  • Professors (Cell Molecular Biology & Plant Science) at Butte College

The skull and cross-bones symbol has been used for a very long time to represent death, perhaps because after death and decomposition, bones are all that remain. Many people think of bones as being dead, dry, and brittle. These adjectives may correctly describe the bones of a preserved skeleton, but the bones of a living human being are very much alive. Living bones are also strong and flexible. Bones are the major organs of the skeletal system.

Figure (PageIndex<1>): skull and cross-bones flag

The skeletal system is the organ system that provides an internal framework for the human body. Why do you need a skeletal system? Try to imagine what you would look like without it. You would be a soft, wobbly pile of skin containing muscles and internal organs but no bones. You might look something like a very large slug. Not that you would be able to see yourself &mdash folds of skin would droop down over your eyes and block your vision because of your lack of skull bones. You could push the skin out of the way if you could only move your arms, but you need bones for that as well!

Components of the Skeletal System

In adults, the skeletal system includes 206 bones, many of which are shown in Figure (PageIndex<2>). Bones are organs made of dense connective tissues, mainly the tough protein collagen. Bones contain blood vessels, nerves, and other tissues. Bones are hard and rigid due to deposits of calcium and other mineral salts within their living tissues. Locations, where two or more bones meet, are called joints. Many joints allow bones to move like levers. For example, your elbow is a joint that allows you to bend and straighten your arm.

Figure (PageIndex<2>): Some of the 206 bones are labeled on the adult human skeleton.

Besides bones, the skeletal system includes cartilage and ligaments.

  • Cartilage is a type of dense connective tissue, made of tough protein fibers. It is strong but flexible and very smooth. It covers the ends of bones at joints, providing a smooth surface for bones to move over.
  • Ligaments are bands of fibrous connective tissue that hold bones together. They keep the bones of the skeleton in place.

Axial and Appendicular Skeletons

The skeleton is traditionally divided into two major parts: the axial skeleton and the appendicular skeleton, both of which are pictured in Figure (PageIndex<3>).

  • The axial skeleton forms the axis of the body. It includes the skull, vertebral column (spine), and rib cage. The bones of the axial skeleton, along with ligaments and muscles, allow the human body to maintain its upright posture. The axial skeleton also transmits weight from the head, trunk, and upper extremities down the back to the lower extremities. In addition, the bones protect the brain and organs in the chest.
  • The appendicular skeleton forms the appendages and their attachments to the axial skeleton. It includes the bones of the arms and legs, hands and feet, and shoulder and pelvic girdles. The bones of the appendicular skeleton make possible locomotion and other movements of the appendages. They also protect the major organs of digestion, excretion, and reproduction.
Figure (PageIndex<3>): Axial skeleton represented in blue Figure (PageIndex<3>): Appendicular skeleton represented in blue

Hypophosphatasia

Routine Studies

Other routine biochemical tests, including serum parameters of liver or muscle function (e.g. bilirubin, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, aldolase), are unremarkable in HPP. Serum acid phosphatase activity is generally normal, 93 but osteoclast-derived tartrate-resistant acid phosphatase was inexplicably elevated for more than a decade in one affected woman. 94 Increased levels of proline in blood and urine have been described in a few patients, but the significance is not known. 95 Bone turnover markers have not yet been detailed in published reports.


Contents

The word homeostasis ( / ˌ h oʊ m i oʊ ˈ s t eɪ s ɪ s / [8] [9] ) uses combining forms of homeo- and -stasis, New Latin from Greek: ὅμοιος homoios, "similar" and στάσις stasis, "standing still", yielding the idea of "staying the same".

The concept of the regulation of the internal environment was described by French physiologist Claude Bernard in 1849, and the word homeostasis was coined by Walter Bradford Cannon in 1926. [10] [11] In 1932, Joseph Barcroft a British physiologist, was the first to say that higher brain function required the most stable internal environment. Thus, to Barcroft homeostasis was not only organized by the brain—homeostasis served the brain. [12] Homeostasis is an almost exclusively biological term, referring to the concepts described by Bernard and Cannon, concerning the constancy of the internal environment in which the cells of the body live and survive. [10] [11] [13] The term cybernetics is applied to technological control systems such as thermostats, which function as homeostatic mechanisms, but is often defined much more broadly than the biological term of homeostasis. [5] [14] [15] [16]

The metabolic processes of all organisms can only take place in very specific physical and chemical environments. The conditions vary with each organism, and with whether the chemical processes take place inside the cell or in the interstitial fluid bathing the cells. The best known homeostatic mechanisms in humans and other mammals are regulators that keep the composition of the extracellular fluid (or the "internal environment") constant, especially with regard to the temperature, pH, osmolality, and the concentrations of sodium, potassium, glucose, carbon dioxide, and oxygen. However, a great many other homeostatic mechanisms, encompassing many aspects of human physiology, control other entities in the body. Where the levels of variables are higher or lower than those needed, they are often prefixed with hyper- and hypo-, respectively such as hyperthermia and hypothermia or hypertension and hypotension.

If an entity is homeostatically controlled it does not imply that its value is necessarily absolutely steady in health. Core body temperature is, for instance, regulated by a homeostatic mechanism with temperature sensors in, amongst others, the hypothalamus of the brain. [17] However, the set point of the regulator is regularly reset. [18] For instance, core body temperature in humans varies during the course of the day (i.e. has a circadian rhythm), with the lowest temperatures occurring at night, and the highest in the afternoons. Other normal temperature variations include those related to the menstrual cycle. [19] [20] The temperature regulator's set point is reset during infections to produce a fever. [17] [21] [22] Organisms are capable of adjusting somewhat to varied conditions such as temperature changes or oxygen levels at altitude, by a process of acclimatisation.

Homeostasis does not govern every activity in the body. [23] [24] For instance the signal (be it via neurons or hormones) from the sensor to the effector is, of necessity, highly variable in order to convey information about the direction and magnitude of the error detected by the sensor. [25] [26] [27] Similarly the effector's response needs to be highly adjustable to reverse the error – in fact it should be very nearly in proportion (but in the opposite direction) to the error that is threatening the internal environment. [15] [16] For instance, the arterial blood pressure in mammals is homeostatically controlled, and measured by stretch receptors in the walls of the aortic arch and carotid sinuses at beginnings of the internal carotid arteries. [17] The sensors send messages via sensory nerves to the medulla oblongata of the brain indicating whether the blood pressure has fallen or risen, and by how much. The medulla oblongata then distributes messages along motor or efferent nerves belonging to the autonomic nervous system to a wide variety of effector organs, whose activity is consequently changed to reverse the error in the blood pressure. One of the effector organs is the heart whose rate is stimulated to rise (tachycardia) when the arterial blood pressure falls, or to slow down (bradycardia) when the pressure rises above set point. [17] Thus the heart rate (for which there is no sensor in the body) is not homeostatically controlled, but is one of effector responses to errors in the arterial blood pressure. Another example is the rate of sweating. This is one of the effectors in the homeostatic control of body temperature, and therefore highly variable in rough proportion to the heat load that threatens to destabilize the body's core temperature, for which there is a sensor in the hypothalamus of the brain.

Core temperature Edit

Mammals regulate their core temperature using input from thermoreceptors in the hypothalamus, brain, [17] [28] spinal cord, internal organs, and great veins. [29] [30] Apart from the internal regulation of temperature, a process called allostasis can come into play that adjusts behaviour to adapt to the challenge of very hot or cold extremes (and to other challenges). [31] These adjustments may include seeking shade and reducing activity, or seeking warmer conditions and increasing activity, or huddling. [32] Behavioural thermoregulation takes precedence over physiological thermoregulation since necessary changes can be affected more quickly and physiological thermoregulation is limited in its capacity to respond to extreme temperatures. [33]

When core temperature falls, the blood supply to the skin is reduced by intense vasoconstriction. [17] The blood flow to the limbs (which have a large surface area) is similarly reduced, and returned to the trunk via the deep veins which lie alongside the arteries (forming venae comitantes). [28] [32] [34] This acts as a counter-current exchange system which short-circuits the warmth from the arterial blood directly into the venous blood returning into the trunk, causing minimal heat loss from the extremities in cold weather. [28] [32] [35] The subcutaneous limb veins are tightly constricted, [17] not only reducing heat loss from this source, but also forcing the venous blood into the counter-current system in the depths of the limbs.

The metabolic rate is increased, initially by non-shivering thermogenesis, [36] followed by shivering thermogenesis if the earlier reactions are insufficient to correct the hypothermia.

When core temperature rises are detected by thermoreceptors, the sweat glands in the skin are stimulated via cholinergic sympathetic nerves to secrete sweat onto the skin, which, when it evaporates, cools the skin and the blood flowing through it. Panting is an alternative effector in many vertebrates, which cools the body also by the evaporation of water, but this time from the mucous membranes of the throat and mouth.

Blood glucose Edit

Blood sugar levels are regulated within fairly narrow limits. [37] In mammals the primary sensors for this are the beta cells of the pancreatic islets. [38] [39] The beta cells respond to a rise in the blood sugar level by secreting insulin into the blood, and simultaneously inhibiting their neighboring alpha cells from secreting glucagon into the blood. [38] This combination (high blood insulin levels and low glucagon levels) act on effector tissues, chief of which are the liver, fat cells and muscle cells. The liver is inhibited from producing glucose, taking it up instead, and converting it to glycogen and triglycerides. The glycogen is stored in the liver, but the triglycerides are secreted into the blood as very low-density lipoprotein (VLDL) particles which are taken up by adipose tissue, there to be stored as fats. The fat cells take up glucose through special glucose transporters (GLUT4), whose numbers in the cell wall are increased as a direct effect of insulin acting on these cells. The glucose that enters the fat cells in this manner is converted into triglycerides (via the same metabolic pathways as are used by the liver) and then stored in those fat cells together with the VLDL-derived triglycerides that were made in the liver. Muscle cells also take glucose up through insulin-sensitive GLUT4 glucose channels, and convert it into muscle glycogen.

A fall in blood glucose, causes insulin secretion to be stopped, and glucagon to be secreted from the alpha cells into the blood. This inhibits the uptake of glucose from the blood by the liver, fats cells and muscle. Instead the liver is strongly stimulated to manufacture glucose from glycogen (through glycogenolysis) and from non-carbohydrate sources (such as lactate and de-aminated amino acids) using a process known as gluconeogenesis. [40] The glucose thus produced is discharged into the blood correcting the detected error (hypoglycemia). The glycogen stored in muscles remains in the muscles, and is only broken down, during exercise, to glucose-6-phosphate and thence to pyruvate to be fed into the citric acid cycle or turned into lactate. It is only the lactate and the waste products of the citric acid cycle that are returned to the blood. The liver can take up only the lactate, and by the process of energy consuming gluconeogenesis convert it back to glucose.

Iron levels Edit

Copper regulation Edit

Levels of blood gases Edit

Changes in the levels of oxygen, carbon dioxide, and plasma pH are sent to the respiratory center, in the brainstem where they are regulated. The partial pressure of oxygen and carbon dioxide in the arterial blood is monitored by the peripheral chemoreceptors (PNS) in the carotid artery and aortic arch. A change in the partial pressure of carbon dioxide is detected as altered pH in the cerebrospinal fluid by central chemoreceptors (CNS) in the medulla oblongata of the brainstem. Information from these sets of sensors is sent to the respiratory center which activates the effector organs – the diaphragm and other muscles of respiration. An increased level of carbon dioxide in the blood, or a decreased level of oxygen, will result in a deeper breathing pattern and increased respiratory rate to bring the blood gases back to equilibrium.

Too little carbon dioxide, and, to a lesser extent, too much oxygen in the blood can temporarily halt breathing, a condition known as apnea, which freedivers use to prolong the time they can stay underwater.

The partial pressure of carbon dioxide is more of a deciding factor in the monitoring of pH. [41] However, at high altitude (above 2500 m) the monitoring of the partial pressure of oxygen takes priority, and hyperventilation keeps the oxygen level constant. With the lower level of carbon dioxide, to keep the pH at 7.4 the kidneys secrete hydrogen ions into the blood, and excrete bicarbonate into the urine. [42] [43] This is important in the acclimatization to high altitude. [44]

Blood oxygen content Edit

The kidneys measure the oxygen content rather than the partial pressure of oxygen in the arterial blood. When the oxygen content of the blood is chronically low, oxygen-sensitive cells secrete erythropoietin (EPO) into the blood. [45] The effector tissue is the red bone marrow which produces red blood cells (RBCs)(erythrocytes). The increase in RBCs leads to an increased hematocrit in the blood, and subsequent increase in hemoglobin that increases the oxygen carrying capacity. This is the mechanism whereby high altitude dwellers have higher hematocrits than sea-level residents, and also why persons with pulmonary insufficiency or right-to-left shunts in the heart (through which venous blood by-passes the lungs and goes directly into the systemic circulation) have similarly high hematocrits. [46] [47]

Regardless of the partial pressure of oxygen in the blood, the amount of oxygen that can be carried, depends on the hemoglobin content. The partial pressure of oxygen may be sufficient for example in anemia, but the hemoglobin content will be insufficient and subsequently as will be the oxygen content. Given enough supply of iron, vitamin B12 and folic acid, EPO can stimulate RBC production, and hemoglobin and oxygen content restored to normal. [46] [48]

Arterial blood pressure Edit

The brain can regulate blood flow over a range of blood pressure values by vasoconstriction and vasodilation of the arteries. [49]

High pressure receptors called baroreceptors in the walls of the aortic arch and carotid sinus (at the beginning of the internal carotid artery) monitor the arterial blood pressure. [50] Rising pressure is detected when the walls of the arteries stretch due to an increase in blood volume. This causes heart muscle cells to secrete the hormone atrial natriuretic peptide (ANP) into the blood. This acts on the kidneys to inhibit the secretion of renin and aldosterone causing the release of sodium, and accompanying water into the urine, thereby reducing the blood volume. [51] This information is then conveyed, via afferent nerve fibers, to the solitary nucleus in the medulla oblongata. [52] From here motor nerves belonging to the autonomic nervous system are stimulated to influence the activity of chiefly the heart and the smallest diameter arteries, called arterioles. The arterioles are the main resistance vessels in the arterial tree, and small changes in diameter cause large changes in the resistance to flow through them. When the arterial blood pressure rises the arterioles are stimulated to dilate making it easier for blood to leave the arteries, thus deflating them, and bringing the blood pressure down, back to normal. At the same time, the heart is stimulated via cholinergic parasympathetic nerves to beat more slowly (called bradycardia), ensuring that the inflow of blood into the arteries is reduced, thus adding to the reduction in pressure, and correction of the original error.

Low pressure in the arteries, causes the opposite reflex of constriction of the arterioles, and a speeding up of the heart rate (called tachycardia). If the drop in blood pressure is very rapid or excessive, the medulla oblongata stimulates the adrenal medulla, via "preganglionic" sympathetic nerves, to secrete epinephrine (adrenaline) into the blood. This hormone enhances the tachycardia and causes severe vasoconstriction of the arterioles to all but the essential organ in the body (especially the heart, lungs, and brain). These reactions usually correct the low arterial blood pressure (hypotension) very effectively.

Calcium levels Edit

The plasma ionized calcium (Ca 2+ ) concentration is very tightly controlled by a pair of homeostatic mechanisms. [53] The sensor for the first one is situated in the parathyroid glands, where the chief cells sense the Ca 2+ level by means of specialized calcium receptors in their membranes. The sensors for the second are the parafollicular cells in the thyroid gland. The parathyroid chief cells secrete parathyroid hormone (PTH) in response to a fall in the plasma ionized calcium level the parafollicular cells of the thyroid gland secrete calcitonin in response to a rise in the plasma ionized calcium level.

The effector organs of the first homeostatic mechanism are the bones, the kidney, and, via a hormone released into the blood by the kidney in response to high PTH levels in the blood, the duodenum and jejunum. Parathyroid hormone (in high concentrations in the blood) causes bone resorption, releasing calcium into the plasma. This is a very rapid action which can correct a threatening hypocalcemia within minutes. High PTH concentrations cause the excretion of phosphate ions via the urine. Since phosphates combine with calcium ions to form insoluble salts (see also bone mineral), a decrease in the level of phosphates in the blood, releases free calcium ions into the plasma ionized calcium pool. PTH has a second action on the kidneys. It stimulates the manufacture and release, by the kidneys, of calcitriol into the blood. This steroid hormone acts on the epithelial cells of the upper small intestine, increasing their capacity to absorb calcium from the gut contents into the blood. [54]

The second homeostatic mechanism, with its sensors in the thyroid gland, releases calcitonin into the blood when the blood ionized calcium rises. This hormone acts primarily on bone, causing the rapid removal of calcium from the blood and depositing it, in insoluble form, in the bones. [55]

The two homeostatic mechanisms working through PTH on the one hand, and calcitonin on the other can very rapidly correct any impending error in the plasma ionized calcium level by either removing calcium from the blood and depositing it in the skeleton, or by removing calcium from it. The skeleton acts as an extremely large calcium store (about 1 kg) compared with the plasma calcium store (about 180 mg). Longer term regulation occurs through calcium absorption or loss from the gut.

Another example are the most well-characterised endocannabinoids like anandamide (N-arachidonoylethanolamide AEA) and 2-arachidonoylglycerol (2-AG), whose synthesis occurs through the action of a series of intracellular enzymes activated in response to a rise in intracellular calcium levels to introduce homeostasis and prevention of tumor development through putative protective mechanisms that prevent cell growth and migration by activation of CB1 and/or CB2 and adjoining receptors. [56]

Sodium concentration Edit

The homeostatic mechanism which controls the plasma sodium concentration is rather more complex than most of the other homeostatic mechanisms described on this page.

The sensor is situated in the juxtaglomerular apparatus of kidneys, which senses the plasma sodium concentration in a surprisingly indirect manner. Instead of measuring it directly in the blood flowing past the juxtaglomerular cells, these cells respond to the sodium concentration in the renal tubular fluid after it has already undergone a certain amount of modification in the proximal convoluted tubule and loop of Henle. [57] These cells also respond to rate of blood flow through the juxtaglomerular apparatus, which, under normal circumstances, is directly proportional to the arterial blood pressure, making this tissue an ancillary arterial blood pressure sensor.

In response to a lowering of the plasma sodium concentration, or to a fall in the arterial blood pressure, the juxtaglomerular cells release renin into the blood. [57] [58] [59] Renin is an enzyme which cleaves a decapeptide (a short protein chain, 10 amino acids long) from a plasma α-2-globulin called angiotensinogen. This decapeptide is known as angiotensin I. [57] It has no known biological activity. However, when the blood circulates through the lungs a pulmonary capillary endothelial enzyme called angiotensin-converting enzyme (ACE) cleaves a further two amino acids from angiotensin I to form an octapeptide known as angiotensin II. Angiotensin II is a hormone which acts on the adrenal cortex, causing the release into the blood of the steroid hormone, aldosterone. Angiotensin II also acts on the smooth muscle in the walls of the arterioles causing these small diameter vessels to constrict, thereby restricting the outflow of blood from the arterial tree, causing the arterial blood pressure to rise. This, therefore, reinforces the measures described above (under the heading of "Arterial blood pressure"), which defend the arterial blood pressure against changes, especially hypotension.

The angiotensin II-stimulated aldosterone released from the zona glomerulosa of the adrenal glands has an effect on particularly the epithelial cells of the distal convoluted tubules and collecting ducts of the kidneys. Here it causes the reabsorption of sodium ions from the renal tubular fluid, in exchange for potassium ions which are secreted from the blood plasma into the tubular fluid to exit the body via the urine. [57] [60] The reabsorption of sodium ions from the renal tubular fluid halts further sodium ion losses from the body, and therefore preventing the worsening of hyponatremia. The hyponatremia can only be corrected by the consumption of salt in the diet. However, it is not certain whether a "salt hunger" can be initiated by hyponatremia, or by what mechanism this might come about.

When the plasma sodium ion concentration is higher than normal (hypernatremia), the release of renin from the juxtaglomerular apparatus is halted, ceasing the production of angiotensin II, and its consequent aldosterone-release into the blood. The kidneys respond by excreting sodium ions into the urine, thereby normalizing the plasma sodium ion concentration. The low angiotensin II levels in the blood lower the arterial blood pressure as an inevitable concomitant response.

The reabsorption of sodium ions from the tubular fluid as a result of high aldosterone levels in the blood does not, of itself, cause renal tubular water to be returned to the blood from the distal convoluted tubules or collecting ducts. This is because sodium is reabsorbed in exchange for potassium and therefore causes only a modest change in the osmotic gradient between the blood and the tubular fluid. Furthermore, the epithelium of the distal convoluted tubules and collecting ducts is impermeable to water in the absence of antidiuretic hormone (ADH) in the blood. ADH is part of the control of fluid balance. Its levels in the blood vary with the osmolality of the plasma, which is measured in the hypothalamus of the brain. Aldosterone's action on the kidney tubules prevents sodium loss to the extracellular fluid (ECF). So there is no change in the osmolality of the ECF, and therefore no change in the ADH concentration of the plasma. However, low aldosterone levels cause a loss of sodium ions from the ECF, which could potentially cause a change in extracellular osmolality and therefore of ADH levels in the blood.

Potassium concentration Edit

High potassium concentrations in the plasma cause depolarization of the zona glomerulosa cells' membranes in the outer layer of the adrenal cortex. [61] This causes the release of aldosterone into the blood.

Aldosterone acts primarily on the distal convoluted tubules and collecting ducts of the kidneys, stimulating the excretion of potassium ions into the urine. [57] It does so, however, by activating the basolateral Na + /K + pumps of the tubular epithelial cells. These sodium/potassium exchangers pump three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid. This creates an ionic concentration gradient which results in the reabsorption of sodium (Na + ) ions from the tubular fluid into the blood, and secreting potassium (K + ) ions from the blood into the urine (lumen of collecting duct). [62] [63]

Fluid balance Edit

The total amount of water in the body needs to be kept in balance. Fluid balance involves keeping the fluid volume stabilized, and also keeping the levels of electrolytes in the extracellular fluid stable. Fluid balance is maintained by the process of osmoregulation and by behavior. Osmotic pressure is detected by osmoreceptors in the median preoptic nucleus in the hypothalamus. Measurement of the plasma osmolality to give an indication of the water content of the body, relies on the fact that water losses from the body, (through unavoidable water loss through the skin which is not entirely waterproof and therefore always slightly moist, water vapor in the exhaled air, sweating, vomiting, normal feces and especially diarrhea) are all hypotonic, meaning that they are less salty than the body fluids (compare, for instance, the taste of saliva with that of tears. The latter has almost the same salt content as the extracellular fluid, whereas the former is hypotonic with respect to the plasma. Saliva does not taste salty, whereas tears are decidedly salty). Nearly all normal and abnormal losses of body water therefore cause the extracellular fluid to become hypertonic. Conversely, excessive fluid intake dilutes the extracellular fluid causing the hypothalamus to register hypotonic hyponatremia conditions.

When the hypothalamus detects a hypertonic extracellular environment, it causes the secretion of an antidiuretic hormone (ADH) called vasopressin which acts on the effector organ, which in this case is the kidney. The effect of vasopressin on the kidney tubules is to reabsorb water from the distal convoluted tubules and collecting ducts, thus preventing aggravation of the water loss via the urine. The hypothalamus simultaneously stimulates the nearby thirst center causing an almost irresistible (if the hypertonicity is severe enough) urge to drink water. The cessation of urine flow prevents the hypovolemia and hypertonicity from getting worse the drinking of water corrects the defect.

Hypo-osmolality results in very low plasma ADH levels. This results in the inhibition of water reabsorption from the kidney tubules, causing high volumes of very dilute urine to be excreted, thus getting rid of the excess water in the body.

Urinary water loss, when the body water homeostat is intact, is a compensatory water loss, correcting any water excess in the body. However, since the kidneys cannot generate water, the thirst reflex is the all-important second effector mechanism of the body water homeostat, correcting any water deficit in the body.

Blood pH Edit

The plasma pH can be altered by respiratory changes in the partial pressure of carbon dioxide or altered by metabolic changes in the carbonic acid to bicarbonate ion ratio. The bicarbonate buffer system regulates the ratio of carbonic acid to bicarbonate to be equal to 1:20, at which ratio the blood pH is 7.4 (as explained in the Henderson–Hasselbalch equation). A change in the plasma pH gives an acid–base imbalance. In acid–base homeostasis there are two mechanisms that can help regulate the pH. Respiratory compensation a mechanism of the respiratory center, adjusts the partial pressure of carbon dioxide by changing the rate and depth of breathing, to bring the pH back to normal. The partial pressure of carbon dioxide also determines the concentration of carbonic acid, and the bicarbonate buffer system can also come into play. Renal compensation can help the bicarbonate buffer system. The sensor for the plasma bicarbonate concentration is not known for certain. It is very probable that the renal tubular cells of the distal convoluted tubules are themselves sensitive to the pH of the plasma. [ citation needed ] The metabolism of these cells produces carbon dioxide, which is rapidly converted to hydrogen and bicarbonate through the action of carbonic anhydrase. [64] When the ECF pH falls (becoming more acidic) the renal tubular cells excrete hydrogen ions into the tubular fluid to leave the body via urine. Bicarbonate ions are simultaneously secreted into the blood that decreases the carbonic acid, and consequently raises the plasma pH. [64] The converse happens when the plasma pH rises above normal: bicarbonate ions are excreted into the urine, and hydrogen ions released into the plasma.

When hydrogen ions are excreted into the urine, and bicarbonate into the blood, the latter combines with the excess hydrogen ions in the plasma that stimulated the kidneys to perform this operation. The resulting reaction in the plasma is the formation of carbonic acid which is in equilibrium with the plasma partial pressure of carbon dioxide. This is tightly regulated to ensure that there is no excessive build-up of carbonic acid or bicarbonate. The overall effect is therefore that hydrogen ions are lost in the urine when the pH of the plasma falls. The concomitant rise in the plasma bicarbonate mops up the increased hydrogen ions (caused by the fall in plasma pH) and the resulting excess carbonic acid is disposed of in the lungs as carbon dioxide. This restores the normal ratio between bicarbonate and the partial pressure of carbon dioxide and therefore the plasma pH. The converse happens when a high plasma pH stimulates the kidneys to secrete hydrogen ions into the blood and to excrete bicarbonate into the urine. The hydrogen ions combine with the excess bicarbonate ions in the plasma, once again forming an excess of carbonic acid which can be exhaled, as carbon dioxide, in the lungs, keeping the plasma bicarbonate ion concentration, the partial pressure of carbon dioxide and, therefore, the plasma pH, constant.

Cerebrospinal fluid Edit

Cerebrospinal fluid (CSF) allows for regulation of the distribution of substances between cells of the brain, [65] and neuroendocrine factors, to which slight changes can cause problems or damage to the nervous system. For example, high glycine concentration disrupts temperature and blood pressure control, and high CSF pH causes dizziness and syncope. [66]

Neurotransmission Edit

Inhibitory neurons in the central nervous system play a homeostatic role in the balance of neuronal activity between excitation and inhibition. Inhibitory neurons using GABA, make compensating changes in the neuronal networks preventing runaway levels of excitation. [67] An imbalance between excitation and inhibition is seen to be implicated in a number of neuropsychiatric disorders. [68]

Neuroendocrine system Edit

The neuroendocrine system is the mechanism by which the hypothalamus maintains homeostasis, regulating metabolism, reproduction, eating and drinking behaviour, energy utilization, osmolarity and blood pressure.

The regulation of metabolism, is carried out by hypothalamic interconnections to other glands. [69] Three endocrine glands of the hypothalamic–pituitary–gonadal axis (HPG axis) often work together and have important regulatory functions. Two other regulatory endocrine axes are the hypothalamic–pituitary–adrenal axis (HPA axis) and the hypothalamic–pituitary–thyroid axis (HPT axis).

The liver also has many regulatory functions of the metabolism. An important function is the production and control of bile acids. Too much bile acid can be toxic to cells and its synthesis can be inhibited by activation of FXR a nuclear receptor. [4]

Gene regulation Edit

At the cellular level, homeostasis is carried out by several mechanisms including transcriptional regulation that can alter the activity of genes in response to changes.

Energy balance Edit

The amount of energy taken in through nutrition needs to match the amount of energy used. To achieve energy homeostasis appetite is regulated by two hormones, grehlin and leptin. Grehlin stimulates hunger and the intake of food and leptin acts to signal satiety (fullness).

A 2019 review of weight-change interventions, including dieting, exercise and overeating, found that body weight homeostasis could not precisely correct for "energetic errors", the loss or gain of calories, in the short-term. [70]

Many diseases are the result of a homeostatic failure. Almost any homeostatic component can malfunction either as a result of an inherited defect, an inborn error of metabolism, or an acquired disease. Some homeostatic mechanisms have inbuilt redundancies, which ensures that life is not immediately threatened if a component malfunctions but sometimes a homeostatic malfunction can result in serious disease, which can be fatal if not treated. A well-known example of a homeostatic failure is shown in type 1 diabetes mellitus. Here blood sugar regulation is unable to function because the beta cells of the pancreatic islets are destroyed and cannot produce the necessary insulin. The blood sugar rises in a condition known as hyperglycemia.

The plasma ionized calcium homeostat can be disrupted by the constant, unchanging, over-production of parathyroid hormone by a parathyroid adenoma resulting in the typically features of hyperparathyroidism, namely high plasma ionized Ca 2+ levels and the resorption of bone, which can lead to spontaneous fractures. The abnormally high plasma ionized calcium concentrations cause conformational changes in many cell-surface proteins (especially ion channels and hormone or neurotransmitter receptors) [71] giving rise to lethargy, muscle weakness, anorexia, constipation and labile emotions. [72]

The body water homeostat can be compromised by the inability to secrete ADH in response to even the normal daily water losses via the exhaled air, the feces, and insensible sweating. On receiving a zero blood ADH signal, the kidneys produce huge unchanging volumes of very dilute urine, causing dehydration and death if not treated.

As organisms age, the efficiency of their control systems becomes reduced. The inefficiencies gradually result in an unstable internal environment that increases the risk of illness, and leads to the physical changes associated with aging. [5]

Various chronic diseases are kept under control by homeostatic compensation, which masks a problem by compensating for it (making up for it) in another way. However, the compensating mechanisms eventually wear out or are disrupted by a new complicating factor (such as the advent of a concurrent acute viral infection), which sends the body reeling through a new cascade of events. Such decompensation unmasks the underlying disease, worsening its symptoms. Common examples include decompensated heart failure, kidney failure, and liver failure.

In the Gaia hypothesis, James Lovelock [73] stated that the entire mass of living matter on Earth (or any planet with life) functions as a vast homeostatic superorganism that actively modifies its planetary environment to produce the environmental conditions necessary for its own survival. In this view, the entire planet maintains several homeostasis (the primary one being temperature homeostasis). Whether this sort of system is present on Earth is open to debate. However, some relatively simple homeostatic mechanisms are generally accepted. For example, it is sometimes claimed that when atmospheric carbon dioxide levels rise, certain plants may be able to grow better and thus act to remove more carbon dioxide from the atmosphere. However, warming has exacerbated droughts, making water the actual limiting factor on land. When sunlight is plentiful and the atmospheric temperature climbs, it has been claimed that the phytoplankton of the ocean surface waters, acting as global sunshine, and therefore heat sensors, may thrive and produce more dimethyl sulfide (DMS). The DMS molecules act as cloud condensation nuclei, which produce more clouds, and thus increase the atmospheric albedo, and this feeds back to lower the temperature of the atmosphere. However, rising sea temperature has stratified the oceans, separating warm, sunlit waters from cool, nutrient-rich waters. Thus, nutrients have become the limiting factor, and plankton levels have actually fallen over the past 50 years, not risen. As scientists discover more about Earth, vast numbers of positive and negative feedback loops are being discovered, that, together, maintain a metastable condition, sometimes within a very broad range of environmental conditions.

Predictive homeostasis is an anticipatory response to an expected challenge in the future, such as the stimulation of insulin secretion by gut hormones which enter the blood in response to a meal. [38] This insulin secretion occurs before the blood sugar level rises, lowering the blood sugar level in anticipation of a large influx into the blood of glucose resulting from the digestion of carbohydrates in the gut. [74] Such anticipatory reactions are open loop systems which are based, essentially, on "guess work", and are not self-correcting. [75] Anticipatory responses always require a closed loop negative feedback system to correct the 'over-shoots' and 'under-shoots' to which the anticipatory systems are prone.

The term has come to be used in other fields, for example:

Risk Edit

An actuary may refer to risk homeostasis, where (for example) people who have anti-lock brakes have no better safety record than those without anti-lock brakes, because the former unconsciously compensate for the safer vehicle via less-safe driving habits. Previous to the innovation of anti-lock brakes, certain maneuvers involved minor skids, evoking fear and avoidance: Now the anti-lock system moves the boundary for such feedback, and behavior patterns expand into the no-longer punitive area. It has also been suggested that ecological crises are an instance of risk homeostasis in which a particular behavior continues until proven dangerous or dramatic consequences actually occur. [76] [ self-published source? ]

Stress Edit

Sociologists and psychologists may refer to stress homeostasis, the tendency of a population or an individual to stay at a certain level of stress, often generating artificial stresses if the "natural" level of stress is not enough. [77] [ self-published source? ]

Jean-François Lyotard, a postmodern theorist, has applied this term to societal 'power centers' that he describes in The Postmodern Condition, as being 'governed by a principle of homeostasis,' for example, the scientific hierarchy, which will sometimes ignore a radical new discovery for years because it destabilizes previously accepted norms.


Concept in Action

View micrographs of musculoskeletal tissues as you review the anatomy.

Cell Types in Bones

Bone consists of four types of cells: osteoblasts, osteoclasts, osteocytes, and osteoprogenitor cells. Osteoblasts are bone cells that are responsible for bone formation. Osteoblasts synthesize and secrete the organic part and inorganic part of the extracellular matrix of bone tissue, and collagen fibers. Osteoblasts become trapped in these secretions and differentiate into less active osteocytes. Osteoclasts are large bone cells with up to 50 nuclei. They remove bone structure by releasing lysosomal enzymes and acids that dissolve the bony matrix. These minerals, released from bones into the blood, help regulate calcium concentrations in body fluids. Bone may also be resorbed for remodeling, if the applied stresses have changed. Osteocytes are mature bone cells and are the main cells in bony connective tissue these cells cannot divide. Osteocytes maintain normal bone structure by recycling the mineral salts in the bony matrix. Osteoprogenitor cells are squamous stem cells that divide to produce daughter cells that differentiate into osteoblasts. Osteoprogenitor cells are important in the repair of fractures.


Role of vasculature in bone regeneration and fracture healing

Orthopaedic surgeons have long appreciated the role of the blood supply in bone growth and healing (2,3). The trauma of a fracture or other major bone injury also damages the blood supply, resulting in local hypoxia, which may be maintained by the subsequent inflammation (34). In rabbits, for example, pO2 in the fracture hematoma is <1% (35) and in the medullary cavity following osteotomy between about 1–3% (36). The HIF-a pathway, which is activated in hypoxia, is reported to be a key mechanism for coupling bone growth to angiogenesis, via increased expression of VEGF, the major angiogenic cytokine expressed by hypoxic osteoblasts. Mice selectively overexpressing HIFa in their osteoblasts had high levels of VEGF expression and extremely dense, highly vascularised bones (37,38). These mice also produced more bone in response to tibial osteotomy and distraction osteogenesis, whereas mice lacking HIF-1a in osteoblasts had impaired VEGF-dependent angiogenesis and bone healing (39). The role of HIFs in osteogenesis may be quite complex, however. A recent report indicates that HIF-1a may also activate expression of sclerostin (the key bone-specific inhibitor of Wnt signaling) in osteoblasts, thus potentially reducing osteogenesis (40). The VEGF homologue, PIGF (placental growth factor), which acts through the VEGF receptor, also appears to play a significant role in promoting fracture healing (34). VEGF stimulates the regrowth of blood vessels into the injury site, so that oxygen and nutrient levels can begin to return to normal values.

The general pattern of bone cell activity following fracture or osteotomy is broadly consistent with the known responses of osteoblasts and osteoclasts to changes in pO2: the early hypoxic phase favours osteoclast recruitment, whilst inhibiting osteoblasts (which may survive locally in a quiescent state), whereas revascularisation will progressively favour osteoblast function (proliferation, differentiation and bone formation). Osteoblast precursors could also move into developing and fractured bones along with invading blood vessels (41). Bone microdamage, induced by fatigue loading, has also been shown to increase local vascularity and blood perfusion, probably as a repair mechanism to reconstruct a disrupted lacuno-canalicular network (42). It is worth noting that application of early or delayed functional loading has been shown to respectively inhibit or stimulate neovascular growth in a rat model of large bone defect regeneration (43). This suggests that biomechanical stimulation could modulate vascular growth and remodelling during bone repair, partially overriding the normal sequence of cellular responses described above.


Biology of MBD and the emerging role of osteocytes

Physiological bone remodeling is highly dependent on the fine-tuned interactions among the bone matrix, osteocytes, osteoclasts, osteoblasts, and immune cells. 6 MBD is characterized by significant deregulation in all these aspects the ultimate effect is increased osteoclast activity and suppressed osteoblast function, leading to bone loss. Osteocytes play a major role in these pathways through the secretion of receptor activator of NF-κB ligand (RANKL), sclerostin, Dickkopf-1 (DKK-1), and other factors that have not been well studied (Figure 1). 7-9 MM cells lead osteocytes to apoptosis to alter the bone marrow microenvironment and provide a premetastatic niche for the MM cells. 10 Indeed, MM patients have reduced number of viable osteocytes, which is associated with increased bone disease burden. 11 In contrast, proteasome inhibitors, which have a positive effect on bone formation in MM, have been shown to restore osteocyte viability by reducing autophagy and apoptosis in MM patients. 12

Schematic overview of MBD. The intercellular interactions between bone marrow stromal cells (BMSCs) and MM cells, along with the involvement of immune cells, such as Th17 cells, induce cytokine release (interleukin-1b [IL-1b], IL-3, IL-6, IL-11, and IL-17) and secretion of proosteoclastogenic factors such as tumor necrosis factor α (TNF-α), chemokine (C-C motif) ligand 3 (CCL3), stromal cell derived factor-1α (SDF-1α), and annexin 2 in the bone marrow microenvironment. These cytokines promote increased osteoclast activity and inhibit osteoblastogenesis. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) on BMSCs and very late antigen-4 (VLA-4) on MM cells mediate cell-to-cell contact. Notch, expressed by MM cells, binds to Jagged, expressed by neighboring MM cells and BMSCs, and activates intracellular cascades favoring RANKL production. RANKL, expressed by both BMSCs and MM cells, binds directly to RANK on osteoclast precursors and promotes osteoclastogenesis. Syndecan-1 on MM cells binds and inactivates osteoprotogerin (OPG), the RANKL soluble decoy receptor. Osteoclasts also produce factors sustaining MM cell growth and survival, such as osteopontin. Furthermore, osteocytes and MM cells produce soluble factors that inhibit osteoblastogenesis such as DKK-1, sFRP-2, and sclerostin. Activin-A secreted by BMSCs also impedes osteoblast production. EphB4 on osteoblasts and BMSCs binds to EphrinB2 on osteoclasts and results in bidirectional signaling that ultimately induces osteoclastogenesis and impedes osteoblastogenesis. Moreover, myeloma cells and osteoclasts produce semaphorin-4D (Sema-4D) and further inhibit the osteoblasts. Osteocyte apoptosis increases RANKL and sclerostin production to increase osteoclast activity, suppress osteoblast differentiation, and increase myeloma growth through bidirectional Notch signaling. BAFF, B cell–activating factor HGF, hepatocyte growth factor. Professional illustration by Somersault18:24.

Schematic overview of MBD. The intercellular interactions between bone marrow stromal cells (BMSCs) and MM cells, along with the involvement of immune cells, such as Th17 cells, induce cytokine release (interleukin-1b [IL-1b], IL-3, IL-6, IL-11, and IL-17) and secretion of proosteoclastogenic factors such as tumor necrosis factor α (TNF-α), chemokine (C-C motif) ligand 3 (CCL3), stromal cell derived factor-1α (SDF-1α), and annexin 2 in the bone marrow microenvironment. These cytokines promote increased osteoclast activity and inhibit osteoblastogenesis. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) on BMSCs and very late antigen-4 (VLA-4) on MM cells mediate cell-to-cell contact. Notch, expressed by MM cells, binds to Jagged, expressed by neighboring MM cells and BMSCs, and activates intracellular cascades favoring RANKL production. RANKL, expressed by both BMSCs and MM cells, binds directly to RANK on osteoclast precursors and promotes osteoclastogenesis. Syndecan-1 on MM cells binds and inactivates osteoprotogerin (OPG), the RANKL soluble decoy receptor. Osteoclasts also produce factors sustaining MM cell growth and survival, such as osteopontin. Furthermore, osteocytes and MM cells produce soluble factors that inhibit osteoblastogenesis such as DKK-1, sFRP-2, and sclerostin. Activin-A secreted by BMSCs also impedes osteoblast production. EphB4 on osteoblasts and BMSCs binds to EphrinB2 on osteoclasts and results in bidirectional signaling that ultimately induces osteoclastogenesis and impedes osteoblastogenesis. Moreover, myeloma cells and osteoclasts produce semaphorin-4D (Sema-4D) and further inhibit the osteoblasts. Osteocyte apoptosis increases RANKL and sclerostin production to increase osteoclast activity, suppress osteoblast differentiation, and increase myeloma growth through bidirectional Notch signaling. BAFF, B cell–activating factor HGF, hepatocyte growth factor. Professional illustration by Somersault18:24.

Increased osteoclast activity

A cardinal signaling cascade regulating osteoclast maturation and activation is the RANK/RANKL pathway. RANKL is produced mainly by osteocytes, but also by activated lymphocytes, BMSCs, and endothelial cells, and promotes osteoclast activity by binding to RANK on the membrane of osteoclastic lineage cells. OPG is secreted by osteoblasts, BMSCs, and osteocytes and antagonizes the interaction between RANKL and RANK. 13,14 MM cells degrade OPG through the membrane syndecan-1 system. 15 Therefore, the increased RANKL/OPG ratio favors bone destruction, and importantly, it affects prognosis of NDMM patients. 16

Another aberrant pathway inducing osteoclast activity is the Notch signaling pathway. Both members of the Notch family and their Jagged ligands are expressed in the membranes of MM cells, enabling homotypical and heterotypical interactions with the same or adjacent cells, respectively. The subsequently activated intracellular cascade ultimately results in the increase of RANKL production by MM cells. However, in the myeloma microenvironment, BMSCs and osteocytes remain the main sources of RANKL. 17,18 Other factors favoring osteoclastogenesis and osteoclast-mediated bone loss include chemokines such as CCL3, SDF-1α, osteopontin, interleukins, annexin 2, members of the transforming growth factor β (TGFβ) superfamily such as activin-A, and members of the TNF superfamily such as TNF-α and BAFF (Figure 1). 19-26

Suppressed osteoblast activity

The Wingless-type (Wnt) and β-catenin pathway is a principal regulator of osteoblast differentiation and bone homeostasis. 27 Osteocytes and MM cells express Wnt antagonists such as sclerostin, DKK-1, and soluble frizzled-related proteins and suppress osteoblast activity. 28,29 Sclerostin is an osteocyte product associated with abnormal bone remodeling it impedes the activation of the canonical Wnt pathway and inhibits osteoblast maturation, impairs bone mineralization, and induces osteoblast apoptosis through caspase cascade activation. 30,31 Sclerostin inhibition with monoclonal antibodies in preclinical MM models restores the deregulated bone metabolism and decreases bone fragility. 29,32 DKK-1 has a synergistic effect with sclerostin and disrupts autocrine Wnt signaling and, subsequently, suppresses osteoblast differentiation and activity. 28,33 Other regulatory factors of the Wnt pathway that are found deregulated in MM include periostin, runt-related transcription factor 2, and growth factor independence-1. 34-36 Furthermore, members of the TGFβ and TNF superfamilies along with interleukins are also implicated in favoring osteoblast suppression, whereas osteoclasts and myeloma cells further inhibit osteoblasts through semaphorin-4D (Figure 1). 37-39 Interestingly, proteasome inhibitors promote osteoblast differentiation by upregulating the intracellular β-catenin pathway independently of Wnt signaling thus, they have an anabolic effect on myelomatous bone. 40-42

Bone marrow microenvironment

In the bone marrow microenvironment, there is a constant crosstalk among the different cell subtypes. 43 Homing of MM cells is favored by their adhesion to BMSCs through the VLA-4/VCAM-1 integrin system. 44 Notch bidirectional signaling also mediates interactions among MM cells, BMSCs, and osteocytes and leads to significant alterations in the bone marrow microenvironment, promoting MM proliferation and bone destruction. 17,18 The dysregulated EphrinB2/EphB4 signaling in MM also impairs the normal interaction between osteoclasts and osteoblasts, which finally results in increased bone loss. 45 Osteoclasts potentiate the immunosuppressive microenvironment by promoting the expansion of Th17 lymphocytes and myeloid-derived suppressor cells, whereas they inhibit the cytotoxic T and NK cells against MM cells. 46,47 The upregulation of immune checkpoint molecules and T-cell metabolism regulators provides the rationale for targeted monoclonal antibodies against programmed death ligand 1 and CD38. 47,48 Interestingly, the interplay between MM cells and mature osteoblasts may provide a unique niche for MM cells to be maintained in quiescence, whereas osteoblast dysfunction or osteoclast remodeling of the endosteal niche allows their reactivation. 49-51


Why Are Ketone Bodies Formed?

When glucose levels are high in your body, it is busy storing the excess as fats, building proteins, and in general growing. This is known as the absorptive state. When you fast, or are being starved, the glucose levels in your blood quickly decrease. This triggers the body to enter the postabsorptive state. In this state, the body starts converting fat back into fatty acids, glycogen into glucose, and even starts breaking down amino acids for energy.

While glycogen is just a storage product of glucose and can be quickly converted back, only so much glycogen is stored in the body (mainly in the liver). Once these stores are depleted, the body must resort to the other breakdown products for energy. Luckily, most of the cells in the body can survive off of fatty acids, created from the breakdown of fat. This is not true, however, for the brain and liver. The brain and liver prefer glucose as a source of energy.

The liver, in order to keep supplying the brain with glucose, must convert amino acids, glycerol, pyruvate, and lactate into glucose. This process is called gluconeogenesis, and also produces the two ketone bodies acetoacetate and beta-hydroxybutyrate. It releases these ketone bodies, along with glucose, into the bloodstream to feed the brain. By this point, the muscles and other organs have mainly switched to fatty acids for energy, conserving the glucose for the brain. This is known as glucose sparing and is very important for animals that must undergo long periods of fasting or starvation.

The brain prefers glucose as a source of energy but will begin to switch to ketone bodies after about 4 days of starvation. This greatly increases the amount of time an organism can go without food, however it can also begin to cause negative side-effects. If food is not eaten to replenish the glucose supply, ketone bodies can begin to build up. While ketone bodies are removed by your kidneys, if they are produced at a high rate they can overwhelm the kidney.


Biology, Physiology, and Morphology of Bone


Osteoblasts are the bone-forming cells that derive from the mesenchymal stem cells of the bone marrow, which also form chondrocytes, myocytes, and adipocytes. Osteoblasts are cuboid-shaped cells that form clusters covering the bone surface. They are metabolically highly active, synthesizing the collagenous and noncollagenous bone matrix proteins, which are excreted and then deposited between the osteoblasts and the bone surface. This newly built matrix, which is not yet calcified, is termed the osteoid. The lag phase between osteoid deposition and its mineralization is approximately 10 days. Osteoblast differentiation depends on the expression of two key transcription factors, Runx2 and its target Osterix 1, which confer the differentiation of these cells into osteoblasts in response to external stimuli. 1 Prostaglandin E 2 (PGE 2 ), insulin-like growth factor (IGF)-1, parathyroid hormone (PTH), bone morphogenic proteins (BMPs), and Wingless and Int-1 (Wnt) proteins are key stimuli for osteoblast differentiation. 2, 3 Prostaglandin E2, for instance, is an important anabolic factor for bone and induces the expression of bone sialoprotein and alkaline phosphatase in mesenchymal cells. Bone morphogenic proteins (BMPs) and transforming growth factor (TGF)-β, which shares structural similarities with BMPs, foster osteoblast differentiation by activating intracellular Smad proteins. Finally, Wnt proteins, a family of highly conserved signaling molecules, are potent stimulators of osteoblast differentiation. Wnt proteins bind to surface receptors on mesenchymal cells such as Frizzled and LRP5, eliciting activation and nuclear translocation of the transcription factor β-catenin, which induces the transcription of genes involved in osteoblast differentiation. Wnts thereby act not only in close synergy with BMPs but also cross-talk to the receptor activator of nuclear factor κB ligand (RANKL)-osteoprotegerin (OPG) system, which is involved in the differentiation and function of bone-resorbing osteoclasts.

Osteoclasts are multinucleated cells containing up to 20 nuclei and are unique in their ability to resorb bone. 6, 7 They are directly attached to the bone surface and build resorption lacunae (Howship’s lacunae). Apart from their multiple nuclei, another characteristic of the osteoclast is the ruffled border, a highly folded plasma membrane facing the bone matrix and designed to secrete and resorb proteins and ions into the space between the osteoclast and bone surface (Figure 4-2). The space between this ruffled border and the bone surface is the place where bone resorption occurs. It is sealed by a ring of contractible proteins and tight junctions because it represents one of the few regions of the human body, where a highly acidic milieu is found. Bone degradation by osteoclasts comprises two major steps: first, demineralization of inorganic bone components, and second, removal of organic bone matrix. To demineralize bone, osteoclasts secrete hydrochloric acid through proton pumps into the resorption lacunae. This proton pump requires energy, which is provided by an ATPase allowing the enrichment of protons in the resorption compartment, which, in fact, represents an extracellular lysosome. In addition to protons and chloride, osteoclasts release matrix-degrading enzymes including tartrate resistant acid phosphatase (TRAP), lysosomal cathepsin K, and other cathepsins. Cathepsin K can effectively degrade collagens and other bone matrix proteins. Consequently, inhibitors of cathepsin K block osteoclast function and slow down bone resorption.


Blood acidity and bones - Biology

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Conclusion

Bone biology is a scientific field that requires an understanding of complex, interrelated areas of study. Detailed knowledge of the anatomy, histology, and physiology of bone tissue has developed dramatically in the last few decades. Our understanding of the process of osteogenesis is constantly under revision, because our knowledge of the genetic and molecular mechanisms controlling bone cell differentiation and growth continues to expand. Much of the impetus behind current bone research is in order to understand the pathogenesis and treatment of diseases such as osteoporosis. Factors such as cytokines, prostaglandins, and mechanical loading, all of which influence and control the local formation and remodeling of bone, have potential to change the way osteoporosis is treated. Future studies are needed to help uncover the mechanobiological rules that help to govern bone response to mechanical loading. 55 A better understanding of these rules will allow physical therapists to be more prescriptive with exercise and level of weight-bearing activity to capitalize on a bone’s inherent ability to remodel.

Both authors provided concept/idea/project design. Dr Downey provided writing. Dr Siegel provided project management and consultation (including review of manuscript before submission).


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