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

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.

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Fig. 1: Deficiency or inhibition of S1P lyase results in higher bone mass and strength, altered OC activity and increased plasma OPG.
Fig. 2: S1P induces OPG secretion in OBs through S1P2.
Fig. 3: S1P activates OB and inhibits adipocyte differentiation through S1P2, and there is reduced adipose tissue mass and adipocyte size in Sgplflox/flox Cre+ mice.
Fig. 4: S1P2 deficiency results in the development of osteopenia and obesity.
Fig. 5: DOP treatment of OVX mice increases trabecular bone volume and mechanical strength, elevates levels of bone formation markers and OPG in plasma and reduces levels of bone resorption markers.
Fig. 6: Association of serum S1P levels and with various bone-related parameters in humans.

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Acknowledgements

We gratefully acknowledge excellent technical help by Kerstin Abou Hamed, forthcoming support by the Zentrales Tierlabor, Universitätsklinikum Essen (G. Hilken, P. Dammann, A. Wissmann, R. Waldschütz) and stimulating discussions with A. Levkau. I dedicate this work to my father, Lubomir Levkau. This work was supported in part by the Deutsche Forschungsgemeinschaft, GRK 2098, projects 9-11 (B.L., P.K.), SFB 1116, projects A08 (J.W.F.) and B02, B05 (U.F.). The work was also supported by the Alexander von Humboldt Foundation through a research fellowship awarded to M.V. The SHIP-Trend study is part of the Community Medicine Research net of the University of Greifswald, Germany, funded by the Federal Ministry of Education and Research (Grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This work was also funded in part by grants from the Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. (B.H.R., M.D., E.S.).

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S.W., M.V., A.R., K.v.W.L., J.K.B., P.K., J.N., M.E., U.F., E.S., M.D., E.M., H.V. and M.S. performed research, collected, analyzed and interpreted data, performed statistical analysis and wrote the manuscript. J.W.F., G.H., M.S. and M.H.G. contributed vital reagents or analytical tools and interpreted data. S.W., A.H., B.H.R. and B.L. designed research, analyzed and interpreted data and wrote the manuscript.

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Correspondence to Bodo Levkau.

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Weske, S., Vaidya, M., Reese, A. et al. Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nat Med 24, 667–678 (2018). https://doi.org/10.1038/s41591-018-0005-y

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