K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling
K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling
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DOI：
10.1016/j.bbrc.2015.02.007
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发表时间：
2015-03-13
影响因子：
3.1
通讯作者：
Fei, Haodong
中科院分区：
文献类型：
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作者：
Ji, Feng;Mao, Li;Fei, Haodong
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（地塞米松（Dex））可直接诱导成骨细胞损伤。在目前的研究中，我们研究了K6 PC-5 [N-（1，3-dihydroxyisopropyl）-2-hexy 1 -3-oxo-decanamide]，一种新的鞘氨醇激酶1（SphK 1）激活剂，对这一过程的潜在活性。我们的数据显示，成骨样MC 3 T3-E1细胞和原代小鼠成骨细胞都对K6 PC-5负责。在培养的成骨细胞中，K6 PC-5激活SphK 1，增加鞘氨醇-1-磷酸（SIP）的产生并诱导Akt磷酸化。在功能上，K6 PC-5保护成骨细胞免受Dex诱导的凋亡和坏死。K6 PC-5的这种信号传导和功能效应被SphK 1抑制剂N，N-二甲基鞘氨醇（DMS）和SphK 1-siRNA阻止。另一方面，外源性SW激活Akt，减少Dex诱导的成骨细胞损伤。LY 294002和MK-2206，两种已建立的Akt抑制剂，减轻K6 PC-5或SIP介导的成骨细胞对Dex的保护。总之，我们的研究结果表明，K6 PC-5通过激活SphK 1-Akt信号转导抑制Dex诱导的成骨细胞损伤。K6 PC-5可能在动物或临床研究中进一步研究其抗糖皮质激素相关骨坏死的潜力。(C)2015 Elsevier Inc. All rights reserved.
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-hexy1-3-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-l-phosphate (SIP) 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 SW activated Akt and reduced Dex-induced osteoblast damages. LY294002 and MK-2206, two established Akt inhibitors, alleviated K6PC-5- or SIP-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. (C) 2015 Elsevier Inc. All rights reserved.