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Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Ernestina Schipani, Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts 02114. E-mail: schipani{at}helix.mgh.harvard.edu.
We all know that control of balance is crucial for survival, and that the otoconial membranes of the vestibule of the ear play an essential role in this process. It is also well known that otoconial membranes are overlaid by small crystals called otoconia (1). The otoconia are biominerals made of a filamentous organic matrix and calcium carbonate (CaCO3). These biominerals are found as large deposits (otholits) in most fish and as numerous small crystals (otoconia) in all other vertebrates. Otoliths and otoconia have been classified in three groups according to the crystalline form of CaCO3: vaterite, aragonite, or calcite. The fundamental requirements for the production of vertebrate otoconia are availability of calcium and carbonate ions. However, the activity of these ions in the endolymphatic space is far too low for spontaneous nucleation. Therefore, mechanisms for localized concentrations of the reactants are required, a role generally played by acidic glycoproteins in other carbonate-based calcification systems. Each type of otoconia is characterized by a distinct set of proteins collectively named otoconins (2, 3, 4). Interestingly, the major proteins of otoconia are related to the secretory phospholipase A2 (2, 3, 4). Why a lypolitic enzyme is required for the formation of small crystals is a question that has not yet been fully answered. Also still largely unknown are the mechanisms that lead to the formation of otoconia and the factors that modulate these mechanisms.
An interesting and provocative paper by Yaoi et al. (5) presented in this issue of Endocrinology sheds light on this problem. When Yaoi et al. cloned a cDNA encoding otoconin-22 from a cDNA library prepared from the endolymphatic sac of bullfrog, they were not surprised, of course, by the finding that bullfrog otoconin-22 was highly homologous to the already cloned Xenopus otoconin-22; what was surprising was to discover that ultimobranchialectomy dramatically reduced the expression of otoconin-22 mRNA. Conversely, supplementation of the ultimobranchialectomized bullfrogs with salmon calcitonin (CT) was able to rescue the expression of otoconin-22 mRNA.
Calcitonin is a 32-amino-acid hormone produced by the parafollicular C cells of the thyroid; these cells are the equivalent of the ultimobranchial gland in frogs, and they originate from the neural crest (6). A tissue-specific alternative splicing of the calcitonin gene results in the production of another peptide, CT-gene-related peptide (CGRP)-1 (6). CT is also related in sequence, at least in mammals, to three other bioactive peptides, adrenomedullin, amylin, and CGRP-2; each of these peptides derives from a separate gene. Bioactivity of the peptides of the CT family is exerted by binding to their receptors. These receptors are G protein-coupled receptors, and their known number is still growing (6). There are two subgroups of receptors for the CT family: CT receptors and CT receptor-like receptors. Each CT family of peptides binds with different affinities to these receptors. To further complicate the picture, accessory proteins act upon these receptors, altering their specific responsivity. These accessory proteins are called receptor activity-modifying proteins (RAMPS) (7).
Whereas CGRP-1 and-2 are established vasodilators and neuromodulators, CT is still a hormone in search of a role (8) in both mammals and lower vertebrates. We have evidence that CT could function as a regulatory hormone in development of lower vertebrates. For example, in Xenopus embryos, addition of CT to the water of developing eggs produces larvae with multiple defects in facial structures and in the nervous system (9, 10); furthermore, overexpression of CT in zebrafish embryos results in axial duplication (11). The study by Yaoi et al. (5) is now the first report of a documented physiological role of CT in lower vertebrates. In mammals, it has been extensively shown that CT binds to a specific G protein-coupled receptor on osteoclasts and inhibits osteoclast function and bone resorption very likely through activation of this receptor (6). However, the physiological significance of CT in skeletal conservation has been challenged, because it is still unexplained why thyroidectomy does not cause, per se, osteoporosis, and why the dramatic high levels of CT in patients with medullary thyroid carcinoma do not trigger osteopetrosis. A recent study has shed light into the role of CT in calcium homeostasis and bone remodeling. This study shows that mice lacking the CT/CGRP gene do not present any developmental defect, but they display an osteoclerotic phenotype mainly linked to a significant augmentation of bone formation (12). Interestingly, the lack of CT/CGRP gene in these mice does not appear to affect basal calcium or other mineral homeostasis, but it significantly increases their responsiveness to exogenous PTH administration. In particular, knockout animals have a greater calcemic response to exogenous PTH than wild-type mice, an effect that is caused by greater bone resorption in knockout animals than in controls. This last finding clearly establishes the physiological role of the CT/CGRP gene in controlling bone resorption and in protecting the bone calcium storage in conditions of increased bone turnover in mammals.
The endolymphatic sac is a major storage site of calcium carbonate in amphibians; it is still an open question whether otoconia turnover in postnatal life does indeed occur; data have been recently reported supporting a model of otoconia as a "dynamic calcium reservoir" (1). CT in amphibians could play a pivotal role in stabilizing this calcium reservoir by increasing otoconin-22 expression. In this regard, therefore, CT in the endolymphatic sac of amphibians would play a role similar to the one in mammalian bone, i.e. protection of the calcium storages. Preliminary findings presented by Yaoi et al. suggest that the receptor implicated in mediating the CT effect on otoconin-22 expression would be a homolog of a CGRP receptor; more studies will be necessary to confirm the data and to elucidate the signaling pathway that leads to the up-regulation of otoconin-22. Another obvious question, then, needs to be addressed: does CT have any role in otoconia formation in mammals?
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Received April 15, 2003.
Accepted for publication April 16, 2003.
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