Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
PLoS One. 2019 Jul 17;14(7):e0219734. doi: 10.1371/journal.pone.0219734. eCollection 2019.
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 μCT, 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.
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了鞘氨醇-1-磷酸（S1P）作为骨重塑偶联因子，它由破骨细胞释放以刺激骨形成。此外，编码五种已知 S1P 受体（S1P3）之一的 S1pr3 在成骨细胞中差异表达，并且 S1P3 缺乏症纠正了骨吸收细胞中 S1P 释放增加的鼠模型（降钙素受体缺陷）的中度高骨量表型。在本研究中，我们解决了这样一个问题，如果 S1P3 缺乏是否也会影响缺乏 S1P-裂合酶（由 Sgpl1 编码）的小鼠的骨骼表型，由于降解不足，这些小鼠表现出明显增加的 S1P 水平。与之前的报道一致，大多数 Sgpl1 缺陷型小鼠在断奶前或断奶后不久死亡，而这种致死性不受额外的 S1P3 缺乏的影响。在 3 周龄时，Sgpl1 缺陷型小鼠表现出增加的小梁骨量，这与增强的破骨细胞生成和骨吸收有关，但也与增加的骨形成有关。然而，最重要的是，通过 μCT、组织形态计量学和血清分析评估的所有骨骼参数均不受额外 S1P3 缺乏的显著影响。总之，我们的发现完全支持 S1P 是一种有效的骨合成代谢分子的概念，尽管 S1P3 不是介导这种影响的唯一受体。由于 S1P 受体被认为是优秀的药物靶点，现在需要筛选其他家族成员对骨形成的影响。
