Ji Feng, Mao Li, Liu Yuanyuan, Cao Xiaojian, Xie Yue, Wang Shouguo, Fei Haodong
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
Biochem Biophys Res Commun. 2015 Mar 13;458(3):568-575. doi: 10.1016/j.bbrc.2015.02.007. Epub 2015 Feb 11.
Long-term glucocorticoid usage is a common cause of non-traumatic femoral head osteonecrosis. Glucocorticoids (i.e. dexamethasone (Dex)) could directly induce damages to osteoblasts. In the current study, we investigated the potential activity of K6PC-5 [N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide], a novel sphingosine kinase 1 (SphK1) activator, against this process. Our data revealed that both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts were responsible to K6PC-5. K6PC-5 activated SphK1, increased sphingosine-1-phosphate (S1P) production and induced Akt phosphorylation in cultured osteoblasts. Functionally, K6PC-5 protected osteoblasts from Dex-induced apoptosis and necrosis. Such signaling and functional effects by K6PC-5 were prevented by the SphK1 inhibitor N,N-dimethylsphingosine (DMS), and by SphK1-siRNAs. On the other hand, exogenously-added S1P activated Akt and reduced Dex-induced osteoblast damages. LY294002 and MK-2206, two established Akt inhibitors, alleviated K6PC-5- or S1P-mediated osteoblast protection against Dex. Together, our results suggest that K6PC-5 alleviates Dex-induced osteoblast injuries through activating SphK1-Akt signaling. K6PC-5 might be further investigated in animal or clinical studies for its anti-glucocorticoids-associated osteonecrosis potential.
长期使用糖皮质激素是非创伤性股骨头坏死的常见原因。糖皮质激素（如地塞米松（Dex））可直接诱导成骨细胞损伤。在本研究中，我们研究了新型鞘氨醇激酶1（SphK1）激活剂K6PC-5 [N-(1,3-二羟基异丙基)-2-己基-3-氧代癸酰胺] 针对这一过程的潜在活性。我们的数据显示，成骨样MC3T3-E1细胞和原代小鼠成骨细胞均对K6PC-5有反应。K6PC-5激活SphK1，增加鞘氨醇-1-磷酸（S1P）生成，并在培养的成骨细胞中诱导Akt磷酸化。在功能上，K6PC-5保护成骨细胞免受Dex诱导的凋亡和坏死。K6PC-5的这种信号传导和功能作用被SphK1抑制剂N,N-二甲基鞘氨醇（DMS）和SphK1小干扰RNA（siRNAs）所阻断。另一方面，外源性添加的S1P激活Akt并减少Dex诱导的成骨细胞损伤。两种已确定的Akt抑制剂LY294002和MK-2206减轻了K6PC-5或S1P介导的成骨细胞对Dex的保护作用。总之，我们的结果表明，K6PC-5通过激活SphK1-Akt信号传导减轻Dex诱导的成骨细胞损伤。K6PC-5因其抗糖皮质激素相关骨坏死的潜力，可能需要在动物或临床研究中进一步研究。
