History. Sir Richard Owen, the curator of the British Museum of Natural History, discovered the parathyroid glands in 1852 while dissecting a rhinoceros that had died in the London Zoo. Credit for discovery of the human parathyroid glands usually is given to Sandstrom, a Swedish medical student who published an anatomical report in 1890. In 1891, von Recklinghausen reported a new bone disease, which he termed "osteitis fibrosa cystica," which Askanazy subsequently described in a patient with a parathyroid tumor in 1904. The glands were rediscovered a decade later by Gley, who determined the effects of their extirpation with the thyroid. Vassale and Generali then successfully removed only the parathyroids and noted that tetany, convulsions, and death quickly followed unless calcium was given postoperatively.
MacCallum and Voegtlin first noted the effect of parathyroidectomy on plasma Ca2+. The relation of low plasma Ca2+ concentration to symptoms was quickly appreciated, and a comprehensive picture of parathyroid function began to form. Active glandular extracts alleviated hypocalcemic tetany in parathyroidectomized animals and raised the level of plasma Ca2+ in normal animals. For the first time, the relation of clinical abnormalities to parathyroid hyperfunction was appreciated.
Whereas American and British investigators used physiological approaches to explore the function of the parathyroid glands, German and Austrian pathologists related the skeletal changes of osteitis fibrosa cystica to the presence of parathyroid tumors; these two investigational approaches arrived at the same conclusions, as has been recounted by Carney (1997).
Chemistry. PTH molecules of all species are all single polypeptide chains of 84 amino acids with molecular masses of ~9500 Da. Biological activity is associated with the N-terminal portion of the peptide; residues 1–27 are required for optimal binding to the PTH receptor and hormone activity. Derivatives lacking the first and second residue bind to PTH receptors but do not activate the cyclic AMP or IP3–Ca2+ signaling pathways. The PTH fragment lacking the first six amino acids inhibits PTH action.
Synthesis, Secretion, and Immunoassay. PTH is synthesized as a 115-amino-acid translation product called preproparathyroid hormone. This single-chain peptide is converted to proparathyroid hormone by cleavage of 25 amino-terminal residues as the peptide is transferred to the intracisternal space of the endoplasmic reticulum. Proparathyroid hormone then moves to the Golgi complex, where it is converted to PTH by cleavage of six amino acids. PTH(1-84) resides within secretory granules until it is discharged into the circulation. Neither preproparathyroid hormone nor proparathyroid hormone appears in plasma. The synthesis and processing of PTH have been reviewed (Jüppner et al., 2001).
A major proteolytic product of PTH is PTH(7–84). PTH(7–84) and other amino-truncated PTH fragments accumulate significantly during renal failure in part because they are normally cleared from the circulation predominantly by the kidneys, whereas intact PTH is also removed by extrarenal mechanisms. Rather than competing with PTH(1–84) binding at the receptor, PTH(7–84) may cause the PTH receptor to internalize from the plasma membrane in a cell-specific manner (Sneddon et al., 2003).
During periods of hypocalcemia, more PTH is secreted and less is hydrolyzed. In this setting, PTH(7–84) release is augmented. In prolonged hypocalcemia, PTH synthesis also increases, and the gland hypertrophies.
PTH(1–84) has a t1/2 in plasma of ~4 minutes; removal by the liver and kidney accounts for ~90% of its clearance. Proteolysis of PTH (in the storage granule and in plasma) generates smaller fragments (e.g., a 33–36 amino acid N-terminal fragment that is fully active, a larger C-terminal peptide, and PTH[7–84]). Much of what circulates in the blood and is measured by older RIAs is the inactive C-terminal fragment that has a longer t1/2 than the active N-terminal fragment or the intact PTH(1–84). Second-generation enzyme-linked immunosorbent assays for PTH, by contrast, can distinguish among these forms, but the clinical value of such information and whether it should affect therapeutic intervention remains controversial (D'Amour, 2008; Herberth et al., 2009).
Physiological Functions. The primary function of PTH is to maintain a constant concentration of Ca2+ and Pi in the extracellular fluid. The principal processes regulated are renal Ca2+ and Pi absorption, and mobilization of bone Ca2+ (Figure 44–3). PTH also affects a variety of tissues not involved in mineral ion homeostasis that include cartilage, vascular smooth muscle, placenta, liver, pancreatic islets, brain, dermal fibroblasts, and lymphocytes. The actions of PTH on its target tissues are mediated by at least two receptors. The PTH1 receptor (PTH1R or PTH/PTHrP receptor) also binds PTH-related protein (PTHrP); the PTH2 receptor, found in vascular tissues, brain, pancreas, and placenta, binds only PTH. Both of these are GPCRs that can couple with Gs and Gq in cell-type specific manners; thus cells may show one, the other, or both types of responses. There is also evidence that PTH can activate phospholipase D through a G12/13–RhoA pathway (Singh et al., 2005). A third receptor, designated the CPTH receptor, interacts with forms of PTH that are truncated in the amino-terminal region, contain most of the carboxy terminus, and are inactive at the PTH1 receptor; these CPTH receptors reportedly are expressed on osteocytes (Selim et al., 2006).
Regulation of Secretion. Plasma Ca2+ is the major factor regulating PTH secretion. As the concentration of Ca2+ diminishes, PTH secretion increases. Sustained hypocalcemia induces parathyroid hypertrophy and hyperplasia. Conversely, if the concentration of Ca2+ is high, PTH secretion decreases. Studies of parathyroid cells in culture show that amino acid transport, nucleic acid and protein synthesis, cytoplasmic growth, and PTH secretion are all stimulated by low concentrations of Ca2+ and suppressed by high concentrations. Thus, Ca2+ itself appears to regulate parathyroid gland growth as well as hormone synthesis and secretion.
Changes in plasma Ca2+ regulate PTH secretion by the plasma membrane–associated calcium-sensing receptor (CaSR) on parathyroid cells. The CaSR is a GPCR that couples with Gq and Gi. Occupancy of the CaSR by Ca2+ thus stimulates the Gq-PLC-IP3-Ca2+ pathway leading to activation of PKC; this results in inhibition of PTH secretion, an unusual case in which elevation of cellular Ca2+ inhibits secretion (another being the granular cells in the juxtaglomerular complex of the kidney, where elevation of cellular Ca2+ inhibits renin secretion). Simultaneous activation of the Gi pathway by Ca2+ reduces cAMP synthesis and lowers the activity of PKA, also a negative signal for PTH secretion. Conversely, reduced occupancy of CaSR by Ca2+ reduces signaling through Gi and Gq, lessening inhibition of adenylyl cyclase and lowering activation of the Gq pathway, thereby promoting PTH secretion. Thus, the extracellular concentration of Ca2+ is controlled by a classical negative-feedback system, the afferent limb of which is sensitive to the ambient activity of Ca2+ and the efferent limb of which releases PTH. Acting via the CaSR, hypercalcemia reduces intracellular cyclic AMP content and activates PKC, whereas hypocalcemia does the reverse. The precise links between these changes and alterations in PTH secretion remain to be defined. Other agents that increase parathyroid cell cyclic AMP levels, such as β adrenergic receptor agonists and dopamine, also increase PTH secretion, but the magnitude of response is far less than that seen with hypocalcemia. The active vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), directly suppresses PTH gene expression. There appears to be no relation between physiological concentrations of extracellular phosphate and PTH secretion, except insofar as changes in phosphate concentration alter circulating Ca2+. Severe hypermagnesemia or hypomagnesemia can inhibit PTH secretion.
Effects on Bone. PTH exerts both catabolic and anabolic effects on bone. Normally, these processes are tightly coupled. Chronically elevated PTH enhances bone resorption and thereby increases Ca2+ delivery to the extracellular fluid, whereas intermittent exposure to PTH promotes anabolic actions. The primary skeletal target cell for PTH is the osteoblast, although evidence points to the presence of functional PTH receptors on osteocytes (O'Brien et al., 2008). PTH also recruits osteoclast precursor cells to form new bone remodeling units. Sustained increases in circulating PTH cause characteristic histological changes in bone that include an increase in the prevalence of osteoclastic resorption sites and in the proportion of bone surface that is covered with unmineralized matrix (Martin and Ng, 1994).
Direct effects of PTH on osteoblasts in vitro generally are inhibitory and include reduced formation of type I collagen, alkaline phosphatase, and osteocalcin. However, the response to PTH in vivo reflects not only hormone action on individual cells but also the increased total number of active osteoblasts, owing to initiation of new remodeling units. Thus, plasma levels of osteocalcin and alkaline phosphatase activity actually may be increased. No simple model can fully explain the molecular basis of PTH effects on bone. PTH stimulates cyclic AMP production in osteoblasts, but there also is evidence that intracellular Ca2+ mediates some PTH actions.
Effects on Kidney. In the kidney, PTH enhances the efficiency of Ca2+ reabsorption, inhibits tubular reabsorption of phosphate, and stimulates conversion of vitamin D to its biologically active form, calcitriol (Figure 44–3). As a result, filtered Ca2+ is avidly retained, and its concentration increases in plasma, whereas phosphate is excreted, and its plasma concentration falls. Newly synthesized calcitriol interacts with specific high-affinity receptors in the intestine to increase the efficiency of intestinal Ca2+ absorption, thereby contributing to the increase in plasma (Ca2+).
Calcium. PTH increases tubular reabsorption of Ca2+ with concomitant decreases in urinary Ca2+ excretion. The effect occurs at distal nephron sites. This action, along with mobilization of calcium from bone and increased absorption from the intestine, increases the concentration of Ca2+ in plasma. Eventually, the increased glomerular filtration of Ca2+ overwhelms the stimulatory effect of PTH on tubular reabsorption, and hypercalciuria ensues. Conversely, reduction of serum PTH depresses tubular reabsorption of Ca2+ and thereby increases urinary Ca2+ excretion. When the plasma Ca2+ concentration falls below 7 mg/dL (1.75 mM), Ca2+ excretion decreases as the filtered load of Ca2+ reaches the point where the cation is almost completely reabsorbed despite reduced tubular capacity.
Phosphate. PTH increases renal excretion of inorganic phosphate by decreasing its reabsorption by proximal tubules. This action is mediated by retrieval of the luminal membrane Na–Pi cotransport protein, NPT2a, rather than an effect on its activity. Patients with primary hyperparathyroidism therefore typically have low tubular phosphate reabsorption.
Cyclic AMP apparently mediates the renal effects of PTH on proximal tubular phosphate reabsorption. PTH-sensitive adenylyl cyclase is located in the renal cortex, and cyclic AMP synthesized in response to the hormone affects tubular transport mechanisms. A portion of the cyclic AMP synthesized at this site, so-called nephrogenous cyclic AMP, escapes into the urine. Measurement of urinary cyclic AMP is used as a surrogate for parathyroid activity and renal responsiveness.
Ions. PTH reduces renal Mg2+ excretion. This effect reflects the net result of enhanced renal Mg2+ reabsorption and increased mobilization of the ion from bone (Quamme, 2010). PTH increases excretion of water, amino acids, citrate, K+, bicarbonate, Na+, Cl–, and SO42–, whereas it decreases the excretion of H+. These effects are minor and generally can be seen only under tightly controlled circumstances.
Calcitriol Synthesis. The final step in the activation of vitamin D to calcitriol occurs in kidney proximal tubule cells. Three primary regulators govern the enzymatic activity of the 25-hydroxyvitamin D3-1α-hydroxylase that catalyzes this step: Pi, PTH, and Ca2+ (see later for further discussion). Reduced circulating or tissue phosphate content rapidly increases calcitriol production, whereas hyperphosphatemia or hypercalcemia suppresses it. PTH powerfully stimulates calcitriol synthesis. Thus, when hypocalcemia causes a rise in PTH concentration, both the PTH-dependent lowering of circulating Pi and a more direct effect of the hormone on the 1α-hydroxylase lead to increased circulating concentrations of calcitriol.
Integrated Regulation of Extracellular Ca2+ Concentration by PTH. Even modest reductions of serum Ca2+ stimulate PTH secretion. For minute-to-minute regulation of Ca2+, adjustments in renal Ca2+ handling more than suffice to maintain plasma calcium homeostasis. With more prolonged hypocalcemia, the renal 1α-hydroxylase is induced, enhancing the synthesis and release of calcitriol that directly stimulates intestinal calcium absorption (Figure 44–3). In addition, delivery of calcium from bone into the extracellular fluid is augmented. In the face of prolonged and severe hypocalcemia, new bone remodeling units are activated to restore circulating Ca2+ concentrations, albeit at the expense of skeletal integrity.
When plasma Ca2+ activity rises, PTH secretion is suppressed, and tubular Ca2+ reabsorption decreases. The reduction in circulating PTH promotes renal phosphate conservation, and both the decreased PTH and the increased phosphate depress calcitriol production and thereby decrease intestinal Ca2+ absorption. Finally, bone remodeling is suppressed. These integrated physiological events ensure a coherent response to positive or negative excursions of plasma Ca2+ concentrations. In humans, the importance of other hormones, such as FGF23 and calcitonin, to this scheme remains unsettled. They may modulate the Ca2+–parathyroid–vitamin D axis or, in the case of FGF23, serve as primary regulators (Razzaque, 2009).