Calcitonin: Physiology or fantasy?

Abstract

Calcitonin, a potent hypocalcemic hormone produced by the C-cells of the thyroid, was first discovered by Harold Copp in 1962. The physiological significance of calcitonin has been questioned, but recent studies using genetically modified mouse models have uncovered additional actions of calcitonin acting through its receptor (CTR) that are of particular significance to the regulation of bone and calcium homeostasis. Mice in which the CTR is deleted in osteoclasts are more susceptible to induced hypercalcemia and exogenous calcitonin is able to lower serum calcium in younger animals. These data are consistent with the hypothesis that calcitonin can regulate serum calcium by inhibiting the efflux of calcium from bone, and that this action is most important when bone turnover is high. Calcitonin has also been implicated in protecting the skeleton from excessive loss of bone mineral during times of high calcium demand, such as lactation. This action may be linked to an intriguing and as yet unexplained observation that calcitonin inhibits bone formation, because deletion of the CTR leads to increased bone formation. We propose several mechanisms by which calcitonin could protect the skeleton by regulating bone turnover, acting within the bone and/or centrally. A new more holistic notion of the physiological role of calcitonin in bone and calcium homeostasis is required and we have highlighted some important knowledge gaps so that future calcitonin research will help to achieve such an understanding.

The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis

“…The presence of peptide hormones from the calcitonin family in the periarticular tissue of loosened implants has raised hopes of establishing new regenerative therapies in the process of aseptic loosening [2,3]. CT has long been known for its important role in protecting the skeleton by regulating bone turnover and maintaining calcium homeostasis [25]. Although previous findings in various genetically modified mouse models support the theory that CT and a-CGRP are potential inhibitors of PIO, there is still debate on the bone regenerative effect of CT in the PIO process [11,12].…”

Calcitonin-Induced Effects on Amniotic Fluid-Derived Mesenchymal Stem Cells

“…It is known that binding of CT to the CTR activates the adenylyl cyclase/cAMP/PKA pathway and/or phospholipase C, which in turn leads to protein kinase C activation/Ca 2+ mobilisation [16,18]. To determine the main pathway activated by this CT stimulation of the huAFMSCs and osteo-differentiated cells, the cAMP and intracellular Ca 2+ levels were measured after 1 nM and 100 nM human CT stimulation (Figs.…”

“…For bone tissue, these signals include hormones, growth factors and mechanical forces, with CT as one of the endocrine signals that is involved in the bone formation/resorption balance. CT mainly acts on osteoclasts [15], but it has also been reported to have effects on osteoblasts and osteocytes [16,19].…”

“…Among the growth factors that modulate bone physiology, calcitonin (CT) has an important role in bone remodelling, as it acts on osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) [13][14][15]. CT functions through limiting the number of osteoclasts and inhibiting their motility and secretory activity [16,17], and by inducing a burst of proliferation and functional activation of osteoblasts [18,19]. Farley and colleagues reported direct effects of CT on different osteoblastic cell models: i.e., murine bone cells [20], human osteosarcoma (SAOS-2, TE-85) cells, and normal human osteoblast-like cells isolated from the head of the femur [21,22].…”

“…Calcitonin-induced activation of the CTR triggers multiple signal transduction pathways that include stimulation of the activities of both adenylyl cyclase/cAMP/protein kinase A (PKA) and phospholipase C, which, in turn, promotes the release of Ca 2+ from intracellular stores and the influx of extracellular Ca 2+ [16,26,27]. Although these signalling pathways have been demonstrated to be mediated by direct binding of the hormone CT to the CTR expressed by osteoclasts [28], the presence of the CTR in osteoblasts still remains unclear and controversial, as well as which signalling cascade is activated by CT [18,29].…”