CLINICAL REVIEW 167 Procalcitonin and the Calcitonin Gene Family of Peptides in Inflammation, Infection, and Sepsis: a Journey from Calcitonin Back to Its Precursors
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0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(4):1512–1525 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2002-021444 CLINICAL REVIEW 167 Procalcitonin and the Calcitonin Gene Family of Peptides in Inflammation, Infection, and Sepsis: A Journey from Calcitonin Back to Its Precursors K. L. BECKER, E. S. NYLE´ N, J. C. WHITE, B. MU¨ LLER, AND R. H. SNIDER, JR. Veterans Affairs Medical Center and George Washington University (K.L.B., E.S.N., J.C.W., R.H.S.), Washington, D.C. 20422; and University Hospitals (B.M.), CH-4031 Basel, Switzerland Calcitonin (CT) is a hormone that received its name be- Immature and mature CT cause of its secretion in response to induced hypercalcemia It had been found that immunoreactive CT was present in and its hypocalcemic effect (1). It was shown to originate multiple heterogeneous forms in MTC tissue as well as in the from the thyroid gland (2). More specifically, the hormone serum of patients with this tumor (20–24). Consequently, it was revealed to be located within the thyroidal parafollicular became apparent that when this peptide was measured with cells, interspersed within and about the follicular epithelium antisera recognizant to different epitopes the values varied (3–5). Subsequently termed C cells, they occur primarily in according to the antiserum and the immunochemical heter- the central region of each lobe of the human thyroid gland ogeneity (25). The phenomenon of heterogeneity was then (6, 7). These cells, which have CT-containing secretion gran- further clarified by a series of studies which demonstrated ules, are neuroendocrine. Embryologically, they originate that CT is biosynthesized as part of a larger prohormone, from the neural crest and migrate to the ultimobranchial procalcitonin (ProCT) (Fig. 1) (21, 23, 25–27). glands (8). In mammals, the ultimobranchial glands fuse The term “mature” hormone has been used to indicate a with the thyroid gland. bioactive hormonal peptide that has been derived from a It was the demonstration that medullary thyroid cancer larger precursor prohormone. This prohormone may be less (MTC) was a malignancy of the C cells (5, 9) that eventually active, inactive, or characterized by an activity that differs led to the isolation of human CT from this tumor and the entirely from the mature hormone. Not uncommonly, much determination of its structure (10, 11). Simultaneously, the of the bioactivity of a mature hormone may be linked to an amino acid sequence of porcine CT was determined (12). amidation that occurs at its carboxyl end. Within ProCT, CT Later, the development of immunoassays of serum CT in is in a nonamidated, immature 33-amino acid form, termi- humans led to the observation that the level of this hor- nating with a glycine (28). It then undergoes posttransla- mone was increased in the serum of patients with MTC tional processing that results in production of several addi- (13–15) and to the demonstration that these levels were tional free peptides as well as mature CT (29–31). further augmented after iv calcium and/or pentagastrin All species of mature CT contain 32 amino acids, with a administration (13, 16, 17). These findings had a great disulfide bridge at the amino terminal end (between amino impact on the clinical diagnosis, the evaluation of efficacy acid positions 1 and 7) and a proline at the carboxyterminal of surgical extirpation, and the follow-up monitoring of end; hence, for the purpose of clarity in this manuscript, the MTC. Although RET germline mutation testing has re- term CT(1–32) will be used specifically to refer to this pep- placed CT for the purpose of determining the presence of tide. Among the various species of CT(1–32), the amino acid carriers of this tumor associated with multiple endocrine sequence of the peptide tends to be well conserved within the neoplasia type 2 (18, 19), the measurement of serum CT has amino acid ring structure at the amino terminus, but there are become and has remained the classical clinical marker for differences elsewhere within the molecule (32–34). At the MTC. carboxyl terminus of the CT(1–32), the proline is amidated (35, 36). Importantly, both the ring structure and this ami- Abbreviations: CCP-I, 21-Amino acid CT carboxyterminus peptide I; dated proline are essential for the full expression of the CGRP, CT gene-related peptide; CT, calcitonin; CTpr, CT precursors; known bioactions of this hormone. LPS, lipopolysaccharide; MTC, medullary thyroid cancer; NO, nitric The accurate quantification of the free CT(1–32) peptide oxide; NProCT, 57-amino acid sequence at the amino terminus of ProCT; requires the selective detection of the amidated carboxyl PNE, pulmonary neuroendocrine (cell); ProCT, procalcitonin; SCLC, small cell cancer of the lung. terminal portion of the molecule, thus excluding the nonami- dated 33-amino acid immature CT, which is found within JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the en- some of the larger molecular weight precursors. Such com- docrine community. mercially available assays were not developed until the late 1512 Downloaded from jcem.endojournals.org by on October 15, 2007 Becker et al. • Clincal Review J Clin Endocrinol Metab, April 2004, 89(4):1512–1525 1513 FIG. 1. Schematic representation of ProCT and the other CT precursors (CTpr) derived from this prohormone (i.e. NProCT, CT-CCP-I, and CCP-I). The mean concentrations of these peptides in normal serum is indicated. Note that there is appreciably more free NProCT in the serum than CT(1–32). In sepsis, the principal elevations involve the intact ProCT, free NProCT, and free conjoined CT-CCP-I peptide. Sequencing reveals that in sepsis, the ProCT may lack the first two amino acids of the aminoterminus of the molecule, presumably due to enzymatic hydrolytic aminoterminal truncation (110), and perhaps other cleavage forms are present as well (111). The comparative extent to which any one of these peptides is increased varies among patients. Levels of the free CCP-I peptide also increase but to a lesser extent. In sepsis, serum CT(1–32) concentrations are undetectable, normal, or only slightly to moderately elevated (data from Ref. 30). 1980s; they use a double-antibody method: one antibody ever, these mice exhibited an increased calcemic response reacts selectively with the amidated region and the other and a greater bone resorption in response to exogenous PTH, with a different portion of the molecule (most commonly the perhaps due to the absence of an otherwise inhibiting effect midportion). Thus, these assays do not cross-react with im- of CT(1–32) on bone resorption. Surprisingly, these knockout mature CT (37–39). In this regard, it is important to empha- mice manifested a markedly increased bone formation; also, size that most CT studies in the literature relating to phys- in contrast to wild-type mice that lose bone mass after ovari- iopharmacologic manipulations as well as such influences as ectomy, they maintained their bone mass. These findings age, gender, pregnancy, and hormonal milieu were not doc- suggest that the CT/CGRP-I gene product may somehow umented with these specific assays. regulate bone formation, either directly or indirectly. Further studies of these interesting observations are needed to de- Physiologic actions of CT termine whether this action is related to CT(1–32), CGRP-I, Hundreds of studies of the possible role of CT(1–32) have or both acting conjointly, and also whether it is species spe- been performed. The great bulk of in vitro and in vivo inves- cific. Additional studies should also determine whether the tigations have involved laboratory animals, some with prior induced knockout results in a compensatory overexpression parathyroidectomy and some without. Often the species of of the gene that gives rise to CGRP-II, which, as a result, may CT(1–32) used in these experiments were other than human conceivably modulate or modify the resultant phenotype. (e.g. salmon, porcine, eel), the amino acid sequences of which The classic and best-studied action of CT(1–32), which differ. Furthermore, pharmacologic, not physiologic, doses appears to occur generally throughout the mammalian spe- often were employed. As a result, many actions have been cies, is the action on the osteoclast (34, 47, 48). Acutely, this incorrectly imputed to this peptide. Known or alleged bio- hormone alters the osteoclast sensitivity to ambient calcium logic actions of CT(1–32) have been reviewed elsewhere (31, and induces quiescence of osteoclast motility and a retraction 33, 40, 41). of the pseudopods that is associated with a cessation of Although seemingly relevant effects have been observed membrane ruffling. The peptide also inhibits the elaboration in blood, bone, kidneys, and the respiratory, gastrointestinal, by the osteoclast of acid phosphatase, carbonic anhydrase II, embryogenic, and central nervous systems (40, 42–45), the focal adhesion kinase, and osteopontin. Possible anabolic function of CT(1–32) in humans remains enigmatic (41). The effects of CT(1–32) on the osteoblast have been reported (49) hormone is not confined to the thyroid gland, and it is im- but require further documentation. The overall impact of the possible to extirpate all cells producing this peptide (see osteoclastic inhibition is to decrease bone resorption (50). below). However, the recent development of a knockout Nevertheless, neither the diminution of serum CT(1–32) oc- mouse in which the coding sequences for both CT(1–32) and curring subsequent to thyroidectomy nor the marked excess CT gene-related peptide (CGRP)-I were deleted have pro- of serum levels of CT(1–32) that occurs in patients with MTC, vided important information (46).