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Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss.
Nature Medicine ( IF 82.9 ) Pub Date : 2018-May-01 , DOI: 10.1038/s41591-018-0005-y
Sarah Weske , Mithila Vaidya , Alina Reese , Karin von Wnuck Lipinski , Petra Keul , Julia K Bayer , Jens W Fischer , Ulrich Flögel , Jens Nelsen , Matthias Epple , Marta Scatena , Edzard Schwedhelm , Marcus Dörr , Henry Völzke , Eileen Moritz , Anke Hannemann , Bernhard H Rauch , Markus H Gräler , Gerd Heusch , Bodo Levkau

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.

中文翻译:

靶向鞘氨醇-1-磷酸裂合酶作为骨代谢的同化疗法。

鞘氨醇-1-磷酸(S1P)信号传导会影响骨骼代谢,但其在骨骼疾病中的治疗潜力尚未得到开发。我们显示,通过有条件地删除或药理抑制S1P裂解酶(负责不可逆降解S1P的唯一酶),提高成年小鼠的S1P水平,显着增加骨形成,质量和强度,并显着减少白色脂肪组织。通过逆向调节osterix和PPAR-γ,通过S1P 2传递的S1P信号通过刺激脂肪形成而有效地刺激了成骨细胞的生成,同时通过新发现的p38-GSK3β-β-catenin和WNT5A-LRP5途径诱导骨保护素,同时抑制了成骨细胞的生成。因此,S1P 2缺乏的小鼠骨质疏松和肥胖。在卵巢切除术引起的骨质减少中,S1P裂解酶抑制与间歇性甲状旁腺激素(iPTH)治疗在增加骨量方面一样有效,在增强骨强度方面优于iPTH。此外,小鼠中的裂解酶抑制可成功纠正由骨保护素缺乏引起的严重遗传性骨质疏松症。来自SHIP-Trend人口研究的4,091名参与者的人类数据显示,血清S1P水平与骨形成标志物(而非吸收标志物)之间呈正相关。此外,血清S1P水平与血清​​钙呈正相关,与PTH呈负相关,与体重指数呈曲线相关。通过定量超声确定的骨刚度与S1P和骨形成标记PINP的含量成反比,提示S1P刺激骨合成代谢活性以抵消骨质量下降。基于S1P的药物应被视为治疗骨质疏松疾病的有前途的治疗途径。
更新日期:2018-04-16
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