An unanticipated role for sphingosine kinase-2 in bone and in the anabolic effect of parathyroid hormone: Supplementary figures

Sphingosine-1-phosphate (S1P) is an anabolic clastokine. SPHK is the rate-limiting enzyme in S1P production and has two isoforms. To evaluate the roles of SPHK1 and SPHK2 in bone, we examined the skeletal phenotype of mice with selective deletion of SPHK1 in osteoclasts (SPHK1-Oc-/-) and mice in which the SPHK2 gene was deleted in all tissues (SPHK2-/-). SPHK1-Oc-/- had normal bone mass. By contrast, SPHK2-/- female mice had a 14% lower spinal BMD (p<0.01) and males a 22% lower BMD at the same site (p<0.001). SPHK2-/- and control mice were subsequently treated either with daily PTH(1-34) or vehicle for 29 days. The response to PTH was significantly attenuated in the SPHK2-/-mice. The mean femoral BV/TV increased by 24.8% in the PTH-treated female control animals vs 10.6% in the vehicle-treated female controls (p <0.01). In contrast, in the SPHK2-/- female mice the difference in femoral trabecular BV/TV at the end of treatment was not significant (20.5 vs.13.3%, PTH vs. vehicle,...

1-磷酸鞘氨醇（Sphingosine-1-phosphate, S1P）是一种合成代谢性破骨细胞因子。鞘氨醇激酶（Sphingosine Kinase, SPHK）是S1P生成过程中的限速酶，存在两种亚型。为评估SPHK1与SPHK2在骨骼中的作用，我们对破骨细胞特异性敲除SPHK1的小鼠（SPHK1-Oc-/-）以及全身组织敲除SPHK2基因的小鼠（SPHK2-/-）的骨骼表型进行了检测。SPHK1-Oc-/-小鼠的骨量未见异常。与之相反，SPHK2-/-雌性小鼠的脊柱骨密度（Bone Mineral Density, BMD）降低14%（P<0.01），雄性小鼠同部位骨密度降低22%（P<0.001）。随后，我们对SPHK2-/-小鼠与对照小鼠每日给予甲状旁腺激素(1-34)（PTH(1-34)）或溶媒处理，持续29天。SPHK2-/-小鼠对PTH的应答显著减弱。经PTH处理的雌性对照小鼠的股骨骨体积/组织体积（Bone Volume/Total Volume, BV/TV）平均升高24.8%，而溶媒处理的雌性对照小鼠仅升高10.6%（P<0.01）。与之相对，SPHK2-/-雌性小鼠在处理结束时的股骨小梁骨BV/TV差异无统计学意义（PTH组与溶媒组分别为20.5%与13.3%，……）