Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

Abstract

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone

“…STAT3 phosphorylation was robustly increased in both osteoclasts and their precursors by IL-6, both in the presence and absence of sIL-6R. However, we could detect no significant alteration in mRNA levels of cardiotrophin-1, Semaphorin 4d, sphingosine 1 kinase, or spinster homologue 2 induced by IL-6 (10 ng/ml) in these cultures (data not shown), suggesting that these previously described coupling factors [17,[53][54][55] are not the osteotransmitters regulated by IL-6. Identifying such factors would require microarray or RNA-Seq analysis and further testing in vitro and in vivo.…”

A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis

“…Taken together, data from these studies allow the proposition that calcitonin has important and related physiological roles in (1) protecting the skeleton by regulating bone metabolism and (2) maintaining calcium homeostasis (9). Specifically, the 2 intriguing actions of calcitonin identified in these studies are its actions to (1) inhibit bone formation (10,11) by inhibiting the release of sphingosine 1-phosphate from osteoclasts (12) and (2) to protect the skeleton during calcium stress, in particular during hypercalcemia (13) mediated primarily via the CTR on osteoclasts (14,15) and in times of high calcium demand such as lactation (16), the latter of which is the focus of this study.…”

Amylin: Pharmacology, Physiology, and Clinical Potential

“…These mice showed increased bone resorption (Turner et al, 2011). Keller et al (2014) also developed mice with osteoclast-specific disruption of calcr, which showed increased bone formation. Although these models give intriguing insight into the physiologic role of the calcitonin receptor in bone biology, none of these models have been carefully evaluated with respect to food intake, body weight, or sensitivity to diet-induced obesity.…”

“…However, studies of this type are often very difficult to interpret due to the complicated receptor system and because sites of calcitonin receptor expression during development are not identical to those in adulthood, as evident from human calcitonin receptor/Lacz transgenic mice (Jagger et al, 2000). Subsequent studies have developed mice with 94%-100% deletion of the calcitonin receptor, using the Cre-LoxP system, targeting exons 13 and 14 or exons 6 and 7 (Davey et al, 2008;Keller et al, 2014). There were no differences in body weight in male or female mice compared with wild-type mice, although the ages at which these measurements were taken were not specified.…”