Deficiency of sphingosine-1-phosphate receptor 3 does not affect the skeletal phenotype of mice lacking sphingosine-1-phosphate lyase
Deficiency of sphingosine-1-phosphate receptor 3 does not affect the skeletal phenotype of mice lacking sphingosine-1-phosphate lyase
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DOI：
10.1371/journal.pone.0219734
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发表时间：
2019-07-17
期刊：
影响因子：
3.7
通讯作者：
Schinke, Thorsten
中科院分区：
文献类型：
--
作者：
Heckt, Timo;Brylka, Laura J.;Schinke, Thorsten
尽管骨质疏松症是老年人群中最常见的疾病之一，但刺激成骨细胞活性的治疗选择仍然有限。我们和其他人之前已经确定鞘氨醇-1-磷酸(S1P)是一种骨重塑偶联因子，它是由骨吸收破骨细胞释放出来的，以刺激骨形成。此外，已知的5种S1P受体(S1P3)之一的S1pr3在成骨细胞中差异表达，S1P3缺乏纠正了小鼠模型(降钙素受体缺乏)的中等高骨量表型，破骨细胞释放S1P增加。在本研究中，我们探讨了S1P3缺乏是否也会影响缺乏S1P裂解酶(由Sgpl1编码)的小鼠的骨骼表型，由于降解不足，S1P水平显著增加。与以前的报告一致，大多数Sgpl1缺陷小鼠在断奶前或之后不久死亡，这种致死性不受额外的S1P3缺陷的影响。在3周龄时，Sgpl1基因缺陷小鼠的骨小梁数量增加，这与破骨细胞生成和骨吸收增强有关，但也与骨形成增加有关。然而，最重要的是，通过MU CT、组织形态计量学和血清分析评估的骨骼参数没有受到额外的S1P3缺乏的显著影响。综上所述，我们的发现完全支持S1P是一种强大的骨合成分子的概念，尽管S1P3不是介导这种影响的唯一受体。由于S1P受体被认为是很好的药物靶点，现在需要筛选其他家庭成员对骨形成的影响。
Albeit osteoporosis is one of the most prevalent disorders in the aged population, treatment options stimulating the activity of bone-forming osteoblasts are still limited. We and others have previously identified sphingosine-1-phosphate (S1P) as a bone remodeling coupling factor, which is released by bone-resorbing osteoclasts to stimulate bone formation. Moreover, S1pr3, encoding one of the five known S1P receptors (S1P3), was found differentially expressed in osteoblasts, and S1P3 deficiency corrected the moderate high bone mass phenotype of a mouse model (deficient for the calcitonin receptor) with increased S1P release from osteoclasts. In the present study we addressed the question, if S1P3 deficiency would also influence the skeletal phenotype of mice lacking S1P-lyase (encoded by Sgpl1), which display markedly increased S1P levels due to insufficient degradation. Consistent with previous reports, the majority of Sgpl1-deficient mice died before or shortly after weaning, and this lethality was not influenced by additional S1P3 deficiency. At 3 weeks of age, Sgpl1-deficient mice displayed increased trabecular bone mass, which was associated with enhanced osteoclastogenesis and bone resorption, but also with increased bone formation. Most importantly however, none of the skeletal parameters assessed by mu CT, histomorphometry and serum analyses were significantly influenced by additional S1P3 deficiency. Taken together, our findings fully support the concept that S1P is a potent osteoanabolic molecule, although S1P3 is not the sole receptor mediating this influence. Since S1P receptors are considered excellent drug targets, it is now required to screen for the impact of other family members on bone formation.