Bone Physiology and Calcium Regulation.pdf

Physiology Dr. Mohamed Balfas Bone Physiology and Calcium Regulation Bone is a living connective tissue. It consists of cells and an extracellular organic matrix (i.e., the substance between cells)...

Physiology Dr. Mohamed Balfas Bone Physiology and Calcium Regulation Bone is a living connective tissue. It consists of cells and an extracellular organic matrix (i.e., the substance between cells) known as osteoid produced by the cells. The bone cells that produce the organic matrix are known as osteoblasts. Osteoid is composed of collagen fibers in a semisolid gel called ground substance. Collagen fibers are embedded in ground substance like steel rebar in reinforced concrete (they give bone flexibility). Bone is made hard by precipitation of calcium phosphate salts (crystals) within the osteoid. These inorganic salts enable bone to support the weight of the body without sagging. Without collagen fibers, a bone is excessively brittle like pieces of chalk, as in osteogenesis imperfecta. When the bones are deficient in inorganic salts, they are soft and bend easily. This is the central problem in the childhood disease rickets. Figure 1: The bone. Three types of bone cells are present in bone. The osteoblasts secrete the extracellular organic matrix (osteoid). The osteocytes are the retired osteoblasts imprisoned within the bony wall they have deposited around themselves. The osteoclasts (macrophage) resorb bone in their vicinity. Microscopic structure of bone: Compact bone forms the dense outer portion of a bone. Trabecular bone (cancellous or spongy bone) make up the inner core of a bone. Compact bone is organized into osteon units, each of which consists of a 1 Physiology Dr. Mohamed Balfas central canal surrounded by concentrically arranged lamellae. Lamellae are layers of osteocytes entombed within the bone they have deposited around themselves. The osteons typically run parallel to the long axis of the bone. Blood vessels penetrate the bone from either the outer surface or the marrow cavity and run through the central canals. Osteoblasts are present in the inner layer of periosteum that covers the outer surface of the bone, in the endosteum (the membrane that lines the medullary marrow cavity), and along the inner surfaces lining the central canals. Osteoclasts are also located under the periosteum and in the endosteum (i.e., on bone surfaces undergoing resorption). In contrast to compact bone tissue, trabecular bone does not contain osteons (Figure 2). Trabecular bone is always located in the interior of a bone, protected by a covering of compact bone. It consists of lamellae that are arranged in an irregular pattern forming trabeculae (meaning 'little beams'). Between the trabeculae are spaces that are visible to the unaided eye. These macroscopic spaces are filled with red bone marrow in bones that produce blood cells, and yellow bone marrow (adipose tissue) in other bones. Figure 2: Microscopic structure of trabecular bone. Endocrine control of calcium (Ca2+): About 99% of the Ca2+ in the body is in crystalline form within the skeleton and teeth. Of the remaining 1%, about 0.9% is found intracellularly within the soft tissues; less than 0.1% is present in the extracellular fluid (ECF). Approximately half of the ECF Ca2+ either is bound to plasma proteins and therefore restricted to the plasma or is complexed with phosphate (PO43-) and not free to participate in chemical reactions. The other half of the ECF Ca2+ is freely diffusible and can readily pass from the plasma into the interstitial fluid and interact with the cells. The free Ca2+ in the plasma and interstitial fluid is considered a single pool. Only this free ECF Ca2+ is biologically active and subject to regulation. Three hormones; parathyroid hormone, calcitonin, and vitamin D control Ca2+ and PO43-. Regulation of plasma Ca2+: Plasma Ca2+ must be closely regulated because it plays a vital role in the following essential activities: 2 Physiology Dr. Mohamed Balfas 1. Neuromuscular excitability; even minor variations in the concentration of free ECF Ca2+ can have a profound and immediate impact on the sensitivity of excitable tissues. A fall in free Ca 2+ results in overexcitability of nerves and skeletal muscles; conversely, a rise in free Ca2+ depresses neuromuscular excitability. These effects result from the influence of Ca2+ on membrane permeability to Na+. A decrease in free Ca2+ increases Na+ permeability, with the resultant influx of Na+ moving the resting potential closer to threshold. Consequently, in the presence of hypocalcemia (low blood Ca2+), excitable tissues may be brought to threshold by normally ineffective physiologic stimuli so that skeletal muscles discharge and contract (go into spasm) “spontaneously” (in the absence of normal stimulation). If severe enough, spastic contraction of the respiratory muscles results in death by asphyxiation. Hypercalcemia (elevated blood Ca2+) causes generalized depression of neuromuscular excitability. 2. Excitation—contraction coupling in cardiac and smooth muscle; entry of ECF Ca2+ into cardiac and smooth muscle cells, resulting from increased Ca2+ permeability in response to an action potential, triggers the contractile mechanism. Ca2+ is also necessary for excitation—contraction coupling in skeletal muscle fibers, but in this case the Ca2+ is released from intracellular Ca2+ endoplasmic reticulum stores in response to an action potential. A significant part of the increase in cytosolic Ca2+ in cardiac muscle cells also derives from internal stores. Important note: An increase in free ECF Ca2+ decreases neuromuscular excitability and reduces the contraction only in skeletal muscles, whereas no reduction in cardiac and smooth muscles contraction occurs as a result of an increase in free ECF Ca2+. This is because there is no real neuromuscular junction in cardiac and smooth muscles like that found in skeletal muscles to be affected by the increase in free ECF Ca2+. Instead, an increase in free ECF Ca2+ has a profound effect especially in cardiac muscle, because more than the usual amount of Ca2+ can diffuse into the cardiac sarcoplasm and this produces strong, prolonged contractions. In extreme cases, it can cause cardiac arrest in systole. Hypocalcemia can cause a weak, irregular heartbeat and potentially cause diastolic arrest. However, severe hypocalcemia is likely to kill through skeletal muscle spastic paralysis and suffocation before the cardiac effects are felt. 3. Stimulus–secretion coupling; the entry of Ca2+ into secretory cells, which results from increased permeability to Ca2+ in response to appropriate stimulation, triggers the release of the secretory product by exocytosis. 4. Clotting of blood; Ca2+ serves as a cofactor in several steps of the cascade of reactions that leads to clot formation. 3 Physiology Dr. Mohamed Balfas Bone remodeling: Bone organic matrix is impregnated with hydroxyapatite crystals consisting primarily of precipitated Ca3(PO4)2 (calcium phosphate) salts. Bone constituents are continually being turned over. Bone deposition (formation) and bone resorption (removal) normally go on concurrently so that bone is constantly being remodeled (adult human skeleton is completely regenerated an estimated every 10 years through remodeling). Bone remodeling serves several physiologically important functions. First, bone ordinarily adjusts its strength in proportion to the degree of bone stress. Consequently, bones thicken when subjected to heavy loads. Second, even the shape of the bone can be rearranged for proper support of mechanical forces by deposition and absorption of bone in accordance with stress patterns. Third, because old bone becomes relatively brittle and weak, new organic matrix is needed as the old organic matrix degenerates. In this manner, the normal toughness of bone is maintained. The large, multinucleated osteoclasts actively secretes hydrochloric acid that dissolves the Ca3(PO4)2 crystals and enzymes that break down the organic matrix. After it has created a cavity, the osteoclast moves on to an adjacent site to burrow another hole. Osteoblasts move into the cavity and secrete osteoid to fill in the hole. Subsequent mineralization of this organic matrix results in new bone to replace the bone dissolved by the osteoclast. Figure 3: Bone remodeling. Control of plasma Ca2+ concentration: Plasma Ca2+ concentration is normally (9.2 to 10.4 mg/dL). Regulation of plasma Ca2+ concentration depends on the hormonal control of exchanges of Ca2+ between the ECF and three other compartments: bone, kidneys, and intestine. Control of Ca2+ encompasses two aspects: First, regulation of calcium homeostasis involves the immediate adjustments required to maintain a constant free plasma Ca2+ concentration on a minute-to-minute basis. This is largely accomplished by rapid exchanges between bone and ECF. Second, regulation of calcium balance involves the more slowly adjustments required to maintain a constant total amount of Ca2+ in the body. Control of Ca2+ balance ensures that Ca2+ intake is equivalent to Ca2+ excretion over the long term (weeks to months). Calcium balance is maintained by adjusting the extent of intestinal Ca2+ absorption and urinary Ca2+ excretion. 4 Physiology Dr. Mohamed Balfas Parathyroid hormone (PTH) is the primary hormone responsible for maintenance of Ca2+ homeostasis and Ca2+ balance by acting directly or indirectly on all three of these sites. Parathyroid hormone raises free plasma Ca2+ levels by its effects on bone, kidneys, and intestine: PTH is a hormone secreted by the parathyroid glands, located on the dorsal surface of the thyroid gland. The overall effect of PTH is to increase the plasma Ca2+ concentration by its actions on bone, kidneys, and intestine, thereby preventing hypocalcemia. PTH is essential for life. In the complete absence of PTH, death ensues within a few days, usually because of asphyxia caused by hypocalcemic spasm of respiratory muscles. This hormone also acts to lower plasma PO43- concentration. Figure 4: Parathyroid hormone raises free plasma Ca2+ levels by its effects on bone, kidneys, and intestine. PTH raises plasma Ca2+ by withdrawing Ca2+ from the bone bank: PTH uses bone as a “bank” from which it withdraws Ca2+ as needed to maintain plasma Ca2+ level. It has two major effects on bone that raise plasma Ca2+ concentration. First, it induces a fast Ca2+ efflux into the plasma from the small labile pool of Ca2+ in the bone fluid. Second, by stimulating bone dissolution, it promotes a slow transfer into the plasma of both Ca2+ and PO43- from the stable pool of bone minerals in bone itself. The immediate effect of PTH is to promote the transfer of Ca2+ from bone fluid into plasma: The surface osteoblasts and entombed osteocytes are connected by an extensive network of small, fluid-containing canals, the canaliculi, which allow substances to be exchanged between trapped osteocytes 5 Physiology Dr. Mohamed Balfas and the circulation. These small canals also contain long, filmy cytoplasmic extensions, or “arms,” of osteocytes and osteoblasts that are connected to one another, much as if these cells were “holding hands.” The “hands” of adjacent cells permit communication and exchange of materials among these bone cells. The interconnecting cell network, which is called the osteocytic—osteoblastic bone membrane, separates the mineralized bone itself from the blood vessels within the central canals. The small, labile pool of Ca2+ is in the bone fluid that lies between this bone membrane and the adjacent bone, both within the canaliculi and along the surface of the central canal. Figure 5: Fast and slow exchanges of Ca2+ across the osteocytic—osteoblastic bone membrane. The earliest effect of PTH is to activate membrane-bound Ca2+ pumps located in the plasma membranes of the osteocytes and osteoblasts. These pumps promote movement of Ca2+, without the accompaniment of PO43-, from the bone fluid into these cells, which in turn transfer the Ca2+ into the plasma within the central canal blood vessels. Movement of Ca2+ out of the labile pool across the bone membrane accounts for the fast exchange between bone and plasma. Although this mechanism provides a rapid defense against changes in free Ca2+ concentrations, it is limited in capacity and can provide for only short-term adjustments in Ca2+ homeostasis. Under conditions of chronic hypocalcemia, such as may occur with dietary Ca2+ deficiency, PTH influences the slow exchange of Ca2+ between bone itself and the ECF by stimulating bone resorption by 6 Physiology Dr. Mohamed Balfas increasing the number and activity of osteoclasts. This demineralization process in the bone releases Ca2+ and PO43- into the blood. PTH acts on the kidneys to conserve Ca2+ and eliminate PO43-: Under the influence of PTH, the kidneys can reabsorb more of the filtered Ca2+, so less Ca2+ escapes into urine. This effect increases the plasma Ca2+ level and decreases urinary Ca2+ losses. By contrast, PTH increases urinary PO43- excretion. As a result, PTH reduces plasma PO43- levels at the same time it increases plasma Ca2+ concentrations. This PTH-induced removal of extra PO43- from the body fluids is essential for preventing re-precipitation of the Ca2+ freed from bone. This prevention of re- precipitation of the Ca2+ is explained by what is known the solubility product. The solubility product: Calcium phosphate salts do not precipitate in tissues unless the product of the plasma concentration of Ca2+ times the plasma concentration of PO43- (Ca2+ X PO43-) exceeds a constant value called the solubility product. Important note; most tissues have inhibitors to prevent calcium phosphate salts precipitation, so they do not become calcified. Osteoblasts, however, apparently neutralize these inhibitors and thus allow the salts to precipitate in the bone matrix. The third important action of PTH on the kidneys (besides increasing Ca2+ reabsorption and increasing PO43- excretion) is to enhance the activation of vitamin D by the kidneys. PTH indirectly promotes absorption of Ca2+ and PO43- by the intestine: Although PTH has no direct effect on the intestine, it indirectly increases both Ca2+ and PO43- absorption from the small intestine by helping activate vitamin D through the stimulation of the enzyme hydroxylase in the kidney. This vitamin, in turn, directly increases intestinal absorption of Ca2+ and PO43-. Furthermore, vitamin D increases the responsiveness of bone to PTH. Vitamin D: Vitamin D is a steroid-like compound essential for Ca2+ absorption in the intestine. The body can obtain vitamin D either by dietary intake or by production in the skin of the body from a precursor related to cholesterol (7 dehydrocholesterol) on exposure to sunlight. 7 Physiology Dr. Mohamed Balfas Figure 6: Activation of vitamin D. Regardless of its source, vitamin D is biologically inactive when it first enters the blood from either the skin or the digestive tract. It must be activated by two sequential biochemical alterations that involve the addition of two hydroxyl (-OH) groups. The first of these reactions occurs in the liver and the second in the kidneys. The end result is production of the active form of vitamin D, 1,25-(OH)2-vitamin D3, also known as calcitriol. The kidney enzymes involved in the second step of vitamin D activation are stimulated by PTH in response to a fall in plasma Ca2+. The primary regulator of PTH secretion is plasma concentration of free Ca2+: PTH secretion increases when plasma Ca2+ falls and decreases when plasma Ca2+ rises. The secretory cells of the parathyroid glands are directly sensitive to changes in free plasma Ca2+. Because PTH regulates plasma Ca2+ concentration, this relationship forms a simple negative—feedback loop for controlling PTH secretion without involving any nervous or other hormonal intervention. 8 Physiology Dr. Mohamed Balfas Calcitonin: This hormone, which is secreted from the thyroid gland, is synthesized by the parafollicular cells (C cells) located between the follicles. The primary effect of calcitonin is to decrease the blood levels of Ca2+ and PO43-. The mechanism of action involves the direct inhibition of osteoclast activity, which decreases bone resorption. This results in less demineralization of the bone and therefore a decrease in the release of Ca2+ and PO43- from the bone into the blood. Calcitonin has no direct effect on bone formation by osteoblasts. The release of calcitonin from the thyroid is regulated by plasma Ca2+ levels through negative feedback. An increase in the level of Ca2+ in the blood stimulates the secretion of calcitonin and a decrease in the level of Ca2+ in the blood inhibits secretion. Figure 7: Negative—feedback controlling PTH and calcitonin secretion. Important note: Hypercalcemia is rare, but hypocalcemia can result from a wide variety of causes including vitamin D deficiency, diarrhea, and thyroid or parathyroid glands tumors. Pregnancy and lactation put women at risk of hypocalcemia because of the Ca2+ demanded by ossification of the fetal skeleton and synthesis of milk. The leading cause of hypocalcemic spasm is accidental removal of the parathyroid glands during thyroid surgery. Clinical pictures of hypocalcemia: 1. Position of the hand in hypocalcemic tetany: Trousseau's sign, a spasm (carpopedal spasm) of the muscles of the upper extremity that causes flexion of the wrist and thumb with extension of the fingers. In individuals with mild tetany in whom spasm is not evident, Trousseau's sign can sometimes be produced by occluding the circulation for a few minutes with a blood pressure cuff. 9 Physiology Dr. Mohamed Balfas Figure 8: Trousseau's sign. 2. Chvostek's sign: A quick contraction of the ipsilateral facial muscles elicited by tapping over the facial nerve at the angle of the jaw, is a sign of tetany in humans. Figure 9: Chvostek's sign. 10