title: K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling.
abstract: 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.
authors: 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.
authors: Feng
authors: F
authors: Ji
authors: Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors: Li
authors: L
authors: Mao
authors: Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors: Yuanyuan
authors: Y
authors: Liu
authors: Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: caoxiaojianmd@126.com.
authors: Xiaojian
authors: X
authors: Cao
authors: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors: Yue
authors: Y
authors: Xie
authors: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors: Shouguo
authors: S
authors: Wang
authors: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors: Haodong
authors: H
authors: Fei
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects*; D005938:Glucocorticoids / Q000009:adverse effects*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000577:Amides; D003907:Dexamethasone; D005938:Glucocorticoids; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D000099157:Sphingosine Kinase; C531172:N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxodecanamide; C060506:sphingosine 1-phosphate
keywords: Akt; Dexamethasone; K6PC-5; Osteoblasts; SphK1; Sphingosine-1-phosphate (S1P)