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University of Utah, Department of Radiobiology, Salt Lake City, Utah 84112
Address all correspondence and requests for reprints to: Dr. Scott Miller, University of Utah, Department of Radiobiology, 729 Arapeen Drive, Room 2334, Salt Lake City, Utah 84112. E-mail: scott.miller{at}hsc.utah.edu.
In 1962 Copp et al. (1) found that thyroid extracts had hypocalcemic properties and named this substance calcitonin (CT). It seemed logical from the early studies to propose that CT was the physiological counterpart to PTH, as PTH has well-established hypercalcemic properties. CT-secreting cells were later found to be of neural crest origin and, in lower vertebrates, concentrated primarily in a specialized gland, the ultimobranchial gland. Manipulation of the ultimobranchial glands helped establish roles for CT in the regulation of fluids, electrolytes, and mineral metabolism in lower vertebrates, including fish, amphibians, and birds (2). The dogma that CT might have similar roles in mammals has persisted, but physiological roles for CT in higher vertebrates have been difficult to prove. Indeed, much of the evidence for physiological roles of CT in mammals has been derived from studies in which pharmacological doses of exogenous CTs, often derived from lower vertebrates such as salmon, were found to blunt bone resorption and reduce blood calcium levels. From these studies, formulations of CT have been developed as therapeutics for such conditions (3).
Perhaps the most compelling argument against a physiological role for CT in mammals is that no conditions or syndromes of CT deficiency or excess have been described. The best example is with medullary thyroid carcinomas where very large amounts of CT may be found in the circulation but without any apparent hypocalcemia. In this regard, native forms of mammalian CT are many times less potent than those derived from lower vertebrates in various assays. This had led to the suggestion that native mammalian CT may be or is becoming a vestigal, nonfunctional remnant of mammalian evolution (4, 5).
There are, however, some observations that do suggest roles for CT in mammalian mineral metabolism. CT, but not PTH, receptors are found in high concentrations on mammalian osteoclasts, suggesting that CT may have a more direct role in the regulation of bone resorption (6). CT might have physiological roles because its production and secretion in mammals, like PTH, is regulated through the calcium-sensing receptor (7). Additionally, levels of CT within the physiological range are able to inhibit osteoclast responses to changes in calcium (8), thus countering effects of PTH on these cells. After all, if CT has no role in higher vertebrates, then why would these elaborate mechanisms of CT regulation and action have persisted throughout the evolution of higher vertebrates?
In this issue of Endocrinology, Woodrow et al. (9) provide some compelling new evidence implicating a role for CT in mammalian mineral metabolism. Specifically, the authors demonstrate a role for CT in the protection of the maternal skeletal during lactation. The mineral requirements for milk production can place substantial metabolic demands on the maternal skeleton, particularly in situations where dietary sources of mineral may be limited (10) (Fig. 1
). Indeed, increases in bone turnover resulting in losses of skeletal mass have been documented in all mammalian species studied (11). Some investigators have suggested that CT might have some protective roles during the mammalian reproductive cycle (12), but the study by Woodrow et al. (9) provides, for the first time, direct experimental evidence in support of this hypothesis.
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(CGRP) null mouse model (Ctcgrp) and examined changes in maternal skeletal mass and structure during the entire reproductive cycle that included pregnancy, lactation, and skeletal reconstitution after weaning. The Ctcgrp null mouse would be completely devoid of CT, including CT derived from extrathyroidal sources. It is the extrathyroidal sources of CT that have clouded the interpretation of previous studies in thyroidectomized women, in whom it was presumed that CT would be completely absent. Surprisingly, however, measurable levels of CT were found during pregnancy and lactation in these women (13).
The Woodrow et al. study (9) shows greater losses in skeletal mass and greater changes in trabecular structure in the Ctcgrp compared with the wild-type siblings. To further document a role for CT, exogenous salmon CT was administered and this normalized the losses in skeletal mass to those observed in the wild type. The replacement of CGRP was without effect, suggesting that it was CT and not the related CGRP peptides that had this mitigating effect on bone mass. This seems to partially counter the argument that the reason that CT has been highly conserved and maintained through evolutionary history is because the alternative splicing of the CT gene produces CGRP, a peptide that may have other important functions in mammalian physiology. If so, then CT could be an incidental byproduct of the production of CGRP in higher vertebrates (4, 5).
In lower vertebrates, CT may function to protect the organism, particularly during certain physiological extremes. CT appears to have roles in fluid regulation, ion exchange, and acid/base balance that may be important, for example, to regulate the osmotic gradient between seawater and extracellular fluids in fish and amphibians (2). Roles for CT have been suggested in the metabolism of avian medullary bone to provide mineral for egg-shell formation during egg-laying in hens and the conservation of phosphate during mineral stresses in other classes of vertebrates. Collectively, these observations suggest that CT may be most important during periods of physiological stress that may include, for example, the osmotic and mineral challenges of a fish returning to the sea after spawning or the mineral stresses associated with an egg-laying cycle or pregnancy and lactation in mammals. The new experimental data provided by Woodrow et al. (9) in this issue of Endocrinology support this view.
Woodrow et al., however, are not the first to use a CT knockout mouse, but they are the first to carefully study the CT null mouse during the reproductive cycle, when the changes in mineral and skeletal metabolism can be extreme. Hoff et al. (14) found, surprisingly, greater bone mass in CT null mice compared with the wild type, a finding that was also observed in the Woodrow et al. study (9). In this regard, there are known adaptations in the mammalian maternal skeleton that appear to help protect the skeleton from periods of calcium stress. These include accumulation of bone mass before the first reproductive period, changes in growth patterns, differential apposition of mineral on specific surfaces, and changes in modeling and remodeling rates to optimize skeletal strength, structure, and metabolism (11, 15). It is possible that CT works in concert with other hormones and factors, such as skeletal loading, to help optimize skeletal structure before, during, and after the mammalian reproductive cycle. CT may work with PTH, for example, before and during pregnancy and with PTHrP during lactation to help the maternal skeleton maintain integrity and strength while also permitting the release of minerals to support the developing fetus during pregnancy and the milk production during lactation.
The bone loss during lactation can be substantial (Fig. 1
), but it is quite unlike that lost in other types of osteopenia, such as ovarian hormone deficiency or immobilization (16) where skeletal integrity may be seriously compromised. During lactation, the maternal skeleton is able to lose remarkable amounts of bone mass, even more than in some other types of osteopenia, yet maintain sufficient bone strength for the prevailing mechanical loads, except in rare circumstances. This "protection" offered to the mammalian maternal skeleton cannot be easily explained by the known actions of established calciotrophic hormones, such as estrogen, PTH, PTHrP, prolactin, and others. The demonstration by Woodrow et al. (9) of a significant role of CT in mammalian skeletal metabolism brings significant new insights, as well as opportunities, to further understand these protective mechanisms and adaptations in the mammalian skeleton. These mechanisms and adaptations may be particularly important during periods of physiological mineral stress, such as the reproductive cycle.
Woodrow et al. (9) also found increased circulating levels of PTH and up-regulation of mammary gland PTHrP mRNA in the Ctcgrp null mice. PTHrP derived from the mammary gland is emerging as an important endocrine regulator of mineral metabolism during lactation (17). The secretion of PTHrP by the mammary gland may help explain prior observations that PTH is not required for successful lactation (18). Also intriguing is the possibility that the mammary gland is also secreting CT during lactation, thus having an endocrine role in addition to a possible local role in modulating the production of PTHrP. CT is produced in large amounts in the mammary gland (19), although if or to what extent the mammary gland may release CT into the systemic circulation is not known. CT is also produced in the pituitary gland and may have paracrine functions in the regulation of PRL secretion (20). However, in the studies on pregnant and lactating women who lacked a thyroid, but had measurable amounts of circulating CT from extrathyroidal sources (13), the mammary gland as a source of this CT is a clear option. Having the mammary gland as the chief regulator of mineral metabolism during lactation certainly makes economic sense in that the animal does not have to rely on the parathyroid gland to ensure an adequate and immediate supply of calcium for milk production. Survival of the species depends on successful and robust reproductive strategies and adaptations. Thus, in this context, the "breast, brain, and bone circuit" in the regulation of mineral and skeletal metabolism during the reproductive cycle, as proposed by Woodrow et al.(9), not only makes sense, but also makes a fertile subject for future research.
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Footnotes |
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, calcitonin gene-related peptide-. Received May 5, 2006.
Accepted for publication May 17, 2006.
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