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Nat Med. 2018 May;24(5):667-678. doi: 10.1038/s41591-018-0005-y. Epub 2018 Apr 16.

Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss.

Author information

1
Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Institute of Pharmacology and Clinical Pharmacology, University of Düsseldorf, Düsseldorf, Germany.
3
Institute of Molecular Cardiology, University of Düsseldorf, Düsseldorf, Germany.
4
Institute of Inorganic Chemistry, University of Duisburg-Essen, Essen, Germany.
5
Department of Bioengineering, University of Washington, Seattle, WA, USA.
6
Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
German Centre for Cardiovascular Research (DZHK), partner site Hamburg, Hamburg, Germany.
8
DZHK, partner site Greifswald, Greifswald, Germany.
9
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
10
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
11
Institute of Pharmacology, Department of General Pharmacology, University Medicine Greifswald, Greifswald, Germany.
12
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
13
Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, and Center for Molecular Biomedicine, University Hospital Jena, Jena, Germany.
14
Institute for Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. bodo.levkau@uni-due.de.

Abstract

Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38-GSK3β-β-catenin and WNT5A-LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases.

PMID:
29662200
DOI:
10.1038/s41591-018-0005-y

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