Translational Implications of the Parathyroid Calcium Receptor
http://www.100md.com
《新英格兰医药杂志》
We live in the era of the Human Genome Project, human and mouse genetics, proteomics, evidence-based medicine, intelligent drug design, and a new "road map" for the National Institutes of Health (NIH) that relies on multidisciplinary, translationally directed teams of basic scientists and clinicians focused on specific goals related to human health. Nonetheless, it is rare indeed that an unanticipated discovery in basic science leads within a decade to the development and commercialization of an entirely new therapeutic class of agents.
It has been known for decades that serum calcium regulates the secretion of parathyroid hormone by the parathyroid glands — a fact that implies the presence of a calcium sensor on the surface of the parathyroid cell. Most researchers in this field assumed that the calcium sensor would turn out to be some kind of calcium-regulated channel. It therefore came as a surprise when, in 1993, Brown and collaborators showed that the calcium-sensing receptor was a G protein–coupled receptor.1 This large class of receptors is exemplified by the thyrotropin receptor and adrenergic receptors that bind large hormones (e.g., thyrotropin) as well as smaller hormones (e.g., catecholamines). The identification of the calcium-sensing receptor as a G protein–coupled receptor was surprising because at the time, no small cation such as calcium had been shown to be capable of acting as a ligand for such a receptor.
A decade has passed, and all now accept the fact that serum calcium binds to the extracellular portion of the calcium-sensing receptor and relays intracellular signals (such as intracellular calcium, protein kinase C, and phosphoinositides) that, in turn, suppress the secretion of parathyroid hormone, with a resultant decrease in the serum calcium concentration. Conversely, when the serum calcium concentration falls, parathyroid hormone secretion is stimulated, resulting in an increase in serum calcium (see Figure). The development of this system of maintaining the serum calcium level within a narrow normal range was central to the development of terrestrial life: without parathyroid hormone, the calcium-sensing receptor, and a skeleton to serve as a reservoir for extracellular calcium, we would all still be in the primeval soup.
Figure. Disease and Therapy Mediated by the Calcium-Sensing Receptor.
The calcium-sensing receptor (CaSR) is represented by the seven-transmembrane-spanning G protein–coupled receptors on the surface of the parathyroid cell. Under normal circumstances, increases in the serum calcium level lead to a suppression of parathyroid hormone (PTH) secretion, resulting in a return to a normal serum calcium level (left). Conversely, reductions in the serum calcium level lead to activation of the CaSR, an increase in PTH secretion, and a resultant increase in the serum calcium level (right). Diseases caused by the activation of the CaSR (bottom left) include autosomal dominant hypoparathyroidism and autoimmune hypocalcemia. Calcimimetic drugs that activate the CaSR are useful in reducing pathologic elevations in PTH. Diseases that are due to the genetic or autoimmune inactivation of the CaSR (bottom right) include familial hypocalciuric hypercalcemia and autoimmune hypercalcemia. The potential use of CaSR-blocking drugs (calcilytics) for osteoporosis is also suggested.
The calcium-sensing receptor was rapidly shown to be central to a number of disorders of mineral metabolism. Inactivating mutations in one allele of the receptor lead to a failure by the parathyroid gland to "sense" increases in serum calcium properly and result in an increase in parathyroid hormone secretion. This is the molecular basis of familial hypocalciuric hypercalcemia (also known as familial benign hypercalcemia). This mild and typically asymptomatic disorder is converted into a severe, life-threatening disorder when two inactivated calcium-sensing–receptor alleles are present. Newborns with this condition, called neonatal severe hyperparathyroidism, have severe hypercalcemia (serum calcium concentration, 15 to 20 mg per deciliter [3.7 to 5.0 mmol per liter]), as well as marked increases in the parathyroid hormone concentration and parathyroid mass, and require urgent parathyroidectomy.
Conversely, activating mutations of the calcium-sensing receptor have been shown to trick the parathyroid gland into "thinking" that the serum calcium level is elevated when it is not. This false message leads to simultaneous reductions in the serum calcium and parathyroid hormone levels. These reductions are the cause of autosomal dominant hypoparathyroidism, a disorder that was once classified as a type of idiopathic hypoparathyroidism. The molecular mechanism and pathophysiology are now understood.
Since G protein–coupled receptors reside on the cell surface, they may be the targets of autoantibodies and cellular immune attack. A good example is the thyrotropin receptor, the target of hyperthyroidism-inducing autoantibodies (thyroid-stimulating immunoglobulins) in Graves' disease and of autoimmune, cell-mediated thyroid destruction and hypothyroidism in Hashimoto's thyroiditis. Could this kind of scenario occur in parathyroid disease? We now know that the calcium-sensing receptor may be one of the targets of cellular and humoral immunity in idiopathic autoimmune hypoparathyroidism.2,3 We have also learned that autoantibodies may functionally activate the calcium-sensing receptor in idiopathic hypoparathyroidism in a scenario parallel to the autoimmune activation of thyrotropin receptors in Graves' disease (see Figure).2 And we have recently learned that autoantibodies that inactivate the calcium-sensing receptor may lead to a syndrome very similar to familial hypocalciuric hypercalcemia.3
In this issue of the Journal, Pallais et al. (pages 362–369) extend this paradigm in a report on a patient with multiple other autoimmune disorders and specific antibodies directed against the calcium-sensing receptor. The patient had intermittent, relapsing hypercalcemia and elevations in the serum parathyroid hormone level, which were responsive to glucocorticoids. Inflammatory involvement of the parathyroid glands was evident at surgery. Why is this disorder not simply primary hyperparathyroidism? Because it relapses, responds to glucocorticoid therapy, and is not associated with identifiable parathyroid disease at surgery. Why is it not just another case of familial hypocalciuric hypercalcemia? Because the serum calcium level was once entirely normal (whereas familial hypocalciuric hypercalcemia is congenital) and because the elevations in the serum calcium and parathyroid hormone levels responded to glucocorticoids.
Clearly, the calcium-sensing receptor is important in rare diseases. But recently, a direct application to a very common disease has emerged. In theory, one could design a small, orally deliverable molecule that mimics the effects of the calcium ion on the calcium-sensing receptor. Such a calcimimetic drug would then tell overactive parathyroid glands to reduce their activity (see Figure). The Food and Drug Administration (FDA) has recently approved cinacalcet, a calcimimetic drug that reduces parathyroid hormone secretion in the secondary hyperparathyroidism that occurs in most patients with chronic renal failure who are receiving dialysis.4 Could cinacalcet reduce parathyroid hormone secretion from parathyroid adenomas in primary hyperparathyroidism? The answer is a tentative yes. Several studies have shown that the drug reduces the elevated calcium levels in primary hyperparathyroidism. This use has not been approved by the FDA.
Conversely, if a calcimimetic drug can lower the parathyroid hormone level, could one develop a drug that would block the calcium-sensing receptor and thereby stimulate parathyroid hormone secretion? That is, could one develop an orally active "calcilytic" drug (see Figure)? This class of drugs is also under development for osteoporosis. When injected daily, parathyroid hormone is highly effective as an anabolic drug for the treatment of osteoporosis. If a calcilytic drug could be developed that would stimulate endogenous parathyroid hormone secretion, one might be able to receive the remarkable anabolic skeletal benefits of parathyroid hormone with a pill rather than requiring an injection.
The story of the calcium-sensing receptor serves as a paradigm for translational research. The discovery involved an iconoclastic theory that was pursued unwaveringly by steadfast researchers, both basic scientists and physician-scientists, supported by the NIH. The discovery led to the elucidation of the pathogenesis of fascinating but rare diseases and permitted biotechnology companies and pharmaceutical firms to develop therapeutic agents for at least one very common disease. All of this has happened within the single decade since the calcium-sensing receptor was first identified in 1993. Few "bench-to-bedside" stories have unfolded with such velocity. And, as the article by Pallais et al. makes clear, the tale remains a work in progress.
Dr. Stewart is the chief executive officer of Osteotrophin and reports having received consulting fees from Eli Lilly.
Source Information
From the Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh.
References
Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995;333:234-240.
Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004;89:548-556.
Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 2003;88:60-72.
Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-1525.(Andrew F. Stewart, M.D.)
It has been known for decades that serum calcium regulates the secretion of parathyroid hormone by the parathyroid glands — a fact that implies the presence of a calcium sensor on the surface of the parathyroid cell. Most researchers in this field assumed that the calcium sensor would turn out to be some kind of calcium-regulated channel. It therefore came as a surprise when, in 1993, Brown and collaborators showed that the calcium-sensing receptor was a G protein–coupled receptor.1 This large class of receptors is exemplified by the thyrotropin receptor and adrenergic receptors that bind large hormones (e.g., thyrotropin) as well as smaller hormones (e.g., catecholamines). The identification of the calcium-sensing receptor as a G protein–coupled receptor was surprising because at the time, no small cation such as calcium had been shown to be capable of acting as a ligand for such a receptor.
A decade has passed, and all now accept the fact that serum calcium binds to the extracellular portion of the calcium-sensing receptor and relays intracellular signals (such as intracellular calcium, protein kinase C, and phosphoinositides) that, in turn, suppress the secretion of parathyroid hormone, with a resultant decrease in the serum calcium concentration. Conversely, when the serum calcium concentration falls, parathyroid hormone secretion is stimulated, resulting in an increase in serum calcium (see Figure). The development of this system of maintaining the serum calcium level within a narrow normal range was central to the development of terrestrial life: without parathyroid hormone, the calcium-sensing receptor, and a skeleton to serve as a reservoir for extracellular calcium, we would all still be in the primeval soup.
Figure. Disease and Therapy Mediated by the Calcium-Sensing Receptor.
The calcium-sensing receptor (CaSR) is represented by the seven-transmembrane-spanning G protein–coupled receptors on the surface of the parathyroid cell. Under normal circumstances, increases in the serum calcium level lead to a suppression of parathyroid hormone (PTH) secretion, resulting in a return to a normal serum calcium level (left). Conversely, reductions in the serum calcium level lead to activation of the CaSR, an increase in PTH secretion, and a resultant increase in the serum calcium level (right). Diseases caused by the activation of the CaSR (bottom left) include autosomal dominant hypoparathyroidism and autoimmune hypocalcemia. Calcimimetic drugs that activate the CaSR are useful in reducing pathologic elevations in PTH. Diseases that are due to the genetic or autoimmune inactivation of the CaSR (bottom right) include familial hypocalciuric hypercalcemia and autoimmune hypercalcemia. The potential use of CaSR-blocking drugs (calcilytics) for osteoporosis is also suggested.
The calcium-sensing receptor was rapidly shown to be central to a number of disorders of mineral metabolism. Inactivating mutations in one allele of the receptor lead to a failure by the parathyroid gland to "sense" increases in serum calcium properly and result in an increase in parathyroid hormone secretion. This is the molecular basis of familial hypocalciuric hypercalcemia (also known as familial benign hypercalcemia). This mild and typically asymptomatic disorder is converted into a severe, life-threatening disorder when two inactivated calcium-sensing–receptor alleles are present. Newborns with this condition, called neonatal severe hyperparathyroidism, have severe hypercalcemia (serum calcium concentration, 15 to 20 mg per deciliter [3.7 to 5.0 mmol per liter]), as well as marked increases in the parathyroid hormone concentration and parathyroid mass, and require urgent parathyroidectomy.
Conversely, activating mutations of the calcium-sensing receptor have been shown to trick the parathyroid gland into "thinking" that the serum calcium level is elevated when it is not. This false message leads to simultaneous reductions in the serum calcium and parathyroid hormone levels. These reductions are the cause of autosomal dominant hypoparathyroidism, a disorder that was once classified as a type of idiopathic hypoparathyroidism. The molecular mechanism and pathophysiology are now understood.
Since G protein–coupled receptors reside on the cell surface, they may be the targets of autoantibodies and cellular immune attack. A good example is the thyrotropin receptor, the target of hyperthyroidism-inducing autoantibodies (thyroid-stimulating immunoglobulins) in Graves' disease and of autoimmune, cell-mediated thyroid destruction and hypothyroidism in Hashimoto's thyroiditis. Could this kind of scenario occur in parathyroid disease? We now know that the calcium-sensing receptor may be one of the targets of cellular and humoral immunity in idiopathic autoimmune hypoparathyroidism.2,3 We have also learned that autoantibodies may functionally activate the calcium-sensing receptor in idiopathic hypoparathyroidism in a scenario parallel to the autoimmune activation of thyrotropin receptors in Graves' disease (see Figure).2 And we have recently learned that autoantibodies that inactivate the calcium-sensing receptor may lead to a syndrome very similar to familial hypocalciuric hypercalcemia.3
In this issue of the Journal, Pallais et al. (pages 362–369) extend this paradigm in a report on a patient with multiple other autoimmune disorders and specific antibodies directed against the calcium-sensing receptor. The patient had intermittent, relapsing hypercalcemia and elevations in the serum parathyroid hormone level, which were responsive to glucocorticoids. Inflammatory involvement of the parathyroid glands was evident at surgery. Why is this disorder not simply primary hyperparathyroidism? Because it relapses, responds to glucocorticoid therapy, and is not associated with identifiable parathyroid disease at surgery. Why is it not just another case of familial hypocalciuric hypercalcemia? Because the serum calcium level was once entirely normal (whereas familial hypocalciuric hypercalcemia is congenital) and because the elevations in the serum calcium and parathyroid hormone levels responded to glucocorticoids.
Clearly, the calcium-sensing receptor is important in rare diseases. But recently, a direct application to a very common disease has emerged. In theory, one could design a small, orally deliverable molecule that mimics the effects of the calcium ion on the calcium-sensing receptor. Such a calcimimetic drug would then tell overactive parathyroid glands to reduce their activity (see Figure). The Food and Drug Administration (FDA) has recently approved cinacalcet, a calcimimetic drug that reduces parathyroid hormone secretion in the secondary hyperparathyroidism that occurs in most patients with chronic renal failure who are receiving dialysis.4 Could cinacalcet reduce parathyroid hormone secretion from parathyroid adenomas in primary hyperparathyroidism? The answer is a tentative yes. Several studies have shown that the drug reduces the elevated calcium levels in primary hyperparathyroidism. This use has not been approved by the FDA.
Conversely, if a calcimimetic drug can lower the parathyroid hormone level, could one develop a drug that would block the calcium-sensing receptor and thereby stimulate parathyroid hormone secretion? That is, could one develop an orally active "calcilytic" drug (see Figure)? This class of drugs is also under development for osteoporosis. When injected daily, parathyroid hormone is highly effective as an anabolic drug for the treatment of osteoporosis. If a calcilytic drug could be developed that would stimulate endogenous parathyroid hormone secretion, one might be able to receive the remarkable anabolic skeletal benefits of parathyroid hormone with a pill rather than requiring an injection.
The story of the calcium-sensing receptor serves as a paradigm for translational research. The discovery involved an iconoclastic theory that was pursued unwaveringly by steadfast researchers, both basic scientists and physician-scientists, supported by the NIH. The discovery led to the elucidation of the pathogenesis of fascinating but rare diseases and permitted biotechnology companies and pharmaceutical firms to develop therapeutic agents for at least one very common disease. All of this has happened within the single decade since the calcium-sensing receptor was first identified in 1993. Few "bench-to-bedside" stories have unfolded with such velocity. And, as the article by Pallais et al. makes clear, the tale remains a work in progress.
Dr. Stewart is the chief executive officer of Osteotrophin and reports having received consulting fees from Eli Lilly.
Source Information
From the Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh.
References
Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995;333:234-240.
Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004;89:548-556.
Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 2003;88:60-72.
Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-1525.(Andrew F. Stewart, M.D.)