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 signalling 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 nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, 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.
Highlights
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
Spns[2] encodes a transmembrane protein involved in the secretion of S1P27,28, which has been shown to function as an osteoanabolic factor coupling bone formation to resorption in vitro[17,18,29]. Since this raised the possibility that the CT receptor (CTR)-dependent control of bone formation is mediated by reducing sphingosine 1-phosphate (S1P) release from osteoclasts, and since other genes with a putative role in osteoclast to osteoblast communication (Sphk[1], Bmp[6], Efnb[2] and Sema4d) were not differentially expressed, we focused on Spns[2] as a relevant downstream target of CT in the control of bone formation
As it was previously demonstrated that protein kinase A (PKA), protein kinase C (PKC) and phospholipase C (PLC) are the major intracellular effectors of CTR-dependent signalling[25,30,31], we investigated which of these pathways is involved in the transcriptional regulation of Spns[2] by CT
Summary
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. Bone resorption was increased in aged Calca-deficient mice, there was a twofold higher bone formation rate at all ages analysed suggesting that the primary physiological function of CT is to limit osteoblast activity. These findings did challenge our understanding of CT as a bone-preserving hormone, they raised several questions of key significance. They suggested that understanding the cellular and molecular mode of CT action would help to identify novel osteoanabolic treatment options
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