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FIGURE 9-14 Functional morphology of an osteoclast. This simplified diagram indicates some of the functional elements of the osteoclast. Numerous receptors for calcitonin and vitronectin are expressed in the plasma membrane. The vitronectin receptors appear to function to facilitate the binding of osteoclasts to bone matrix; the receptor utilizes the recognition sequence of Arg-Gly-Asp on the bone matrix protein. Osteoclasts possess a significant level of tartrate-resistant acid phosphatase (TRAP), which has been used as a specific histochemical marker of osteoclasts. The basolateral membrane has ATP-dependent ion transport systems to extrude calcium and maintain intracellular potassium, similar to other cells. The osteoclast is enriched in mitochondria to provide the large amount of ATP necessary for these pumps as well as for an electrogenic proton pump, which raises the hydrogen ion concentration at the ruffled border area. Lysosomal enzymes are synthesized and taken up in Golgi vesicles that contain mannose 6-phosphate receptors. These vesicles presumably circulate through the cell, discharging their enzyme contents into the ruffled border area. The sealing zone, with its actin filaments and specialized attachment structures (podosomes), surrounds the ruffled border area and separates it from the extracellular fluid. Carbonic acid is generated from the C02 produced by mitochondrial metabolism and provides the source for hydrogen ions. The excess HC03~ is removed by exchange with chloride. [Reproduced with permission from Suda, T., Takahashi, N., and Martin, T. J. (1992). Modulation of osteoclast differentiation. Endocr. Rev. 1, 66-80.]

One model of bone resorption and formation describes a "bone remodeling unit," which comprises the integrated and sequential actions of osteoclasts and osteoblasts. The detailed functioning of this model through the phases of activation, resorption, reversal, formation, and mineralization is described in Figure 9-13 and Table 9-6. Also, a model for the functional operation of the osteoclast is presented in Figure 9-14.

Although the dominant activators of bone resorption and osteoclast activation are PTH and la,25(OH)2D3, intriguingly, the osteoclast does not have a receptor for either of these hormones. Thus, the activation process involving PTH is believed to occur as a consequence of PTH interacting with its receptor on the osteoblast. Then the activated osteoblast releases paracrine agents, whose nature has not been precisely defined, which then achieve activation of the osteoclast, so that the bone-resorptive event is initiated. In contrast, the actions of la,25(OH)2D3 to increase bone resorption are believed to be mediated more distally by increasing a hematopoietic cell differentiation process (see Figure 9-12) to produce increased numbers of osteoclasts. The osteoclast, however, has receptors for calcitonin, and occupancy of this receptor leads to a reduction in bone resorption.

Bone formation is achieved through the activation of the osteoblast. la,25(OH)2D3, through the actions of its nVDR in the osteoblast, is a major stimulator of transcription, leading to increased biosynthesis of collagen, osteocalcin, and other matrix proteins. The detailed steps of osteoblast-mediated Ca2+ transport and bone mineralization are not yet known.

F. Integrated Actions of Parathyroid Hormone, Calcitonin, and Vitamin D Metabolites

The maintenance of calcium and phosphorus homeostasis involves the integration of absorption by the intestine, accretion and reabsorption by bone tissue, and urinary excretion of these two ions by the kidney. Table 9-7 summarizes the physiological effects of calcitonin, parathyroid hormone, and vitamin D metabolites in these three organs. The steroid la,25(OH)2D3 plays a dominant role in increasing the intestinal absorption of calcium and phosphorus; however, this uptake process is regulated carefully according to the needs of the animal and is dictated by certain physiological signals, which are dependent in large part on the plasma levels of calcium and possibly phosphorus. Once calcium and phosphate enter into the plasma, a delicate balancing operation occurs between accretion and mobilization in the bone and between excretion and reabsorption by the kidney. In the event that the dietary intake or availability of calcium and phosphorus is diminished or increased, it is possible to tip the balance in favor of increased bone mobilization or

TABLE 9-7 Physiological Effects of Calcitonin, Parathyroid Hormone, and Vitamin D (Metabolites) Related to Mineral Metabolism"

Calcitonin

Parathyroid hormone ltt,25(OH)2D3

Intestinal

Calcium absorption Phosphate absorption

Renal

Phosphate excretion Calcium excretion Adenyl cyclase activity

Skeletal Calcium mobilization Mineralization of bone matrix

Other

Plasma levels of calcium Plasma levels of phosphate i ? ?

f (indirect)

" The important role of bone as a central organ in calcium and phosphorus metabolism, acting both as a source of and a reservoir for these two ions, is discussed in the text. It is apparent that bone remodeling processes may contribute to both short- and long-term events necessary for calcium and phosphorus homeostasis. The relative actions of bone formation and resorption are known to be modulated by various endocrine regulators during times of skeletal growth and lactation and in birds during the process of egg laying. Also, it is not surprising that bone is involved in a wide variety of disease states that reflect perturbations in calcium and phosphorus homeostasis.

increased urinary excretion, respectively, to meet the stringent requirement of a constant serum calcium level. Thus, serum calcium may become elevated by PTH-la,25(OH)2D-mediated stimulation of bone calcium mobilization or by parathyroid hormone stimulation of the tubular reabsorption of calcium at the kidney. Concomitantly, PTH also stimulates urinary phosphate excretion, so that as the serum calcium concentration increases, there is usually an associated reduction in the plasma phosphate level. This then prevents the inappropriate precipitation of calcium phosphate in soft tissues, which would be the logical consequence of exceeding the solubility product, Ksp/ for [calcium] x [phosphate].

When serum calcium levels become too elevated, the action of calcitonin may come into play. Simply speaking, calcitonin is believed to block many of the actions of PTH at the skeletal level, thereby preventing further elevation of serum calcium levels. Secretion of calcitonin may be stimulated during intervals of gastrointestinal absorption of calcium to prevent short-term intervals of hypercalcemia. Also associated with the increased secretion of calcitonin is an increase in calcium excretion by the kidney, which can contribute to a reduction in the circulating levels of serum calcium and prevent soft tissue calcification.

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