Brain-derived neurotrophic factor protects cementoblasts from serum starvation-induced cell death.
Our previous studies have shown that brain-derived neurotrophic factor (BDNF) enhances bone/cementum-related protein gene expression through the TrkB-c-Raf-ERK1/2-Elk-1 signaling pathway in cementoblasts, which play a critical role in the establishment of a functional periodontal ligament. To clarify how BDNF regulates survival in cementoblasts, we examined its effects on cell death induced by serum starvation in immortalized human cementoblast-like (HCEM) cells. BDNF inhibited the death of HCEM cells. Small-interfering RNA (siRNA) for TRKB, a high affinity receptor for BDNF, and for Bcl-2, countered the BDNF-induced decrease in dead cell number. In addition, LY294002, a PI3-kinase inhibitor; SH-6, an Akt inhibitor; and PDTC, a nuclear factor kappa B (NF-kappaB) inhibitor, but not PD98059, an ERK1/2 inhibitor, abolished the protective effect of BDNF against cell death. BDNF enhanced phosphorylated Akt levels, NF-kappaB activity in the nucleus, Bcl-2 mRNA levels, and mitochondrial membrane potential. The blocking of BDNF's actions by treatment with siRNA in all cases for TRKB and Bcl-2, LY294002, SH-6, and PDTC suppressed the enhancement. These findings provide the first evidence that a TrkB-PI3-kinase-Akt-NF-kappaB-Bcl-2 signaling pathway triggered by BDNF and the subsequent protective effect of BDNF on mitochondrial membrane potential are required to rescue HCEM cells from serum starvation-induced cell death. Furthermore, the survival and increased expression of bone/cementum-related proteins induced by BDNF in HCEM cells occur through different signaling pathways.
Kajiya
Mikihito
M
Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Shiba
Hideki
H
Fujita
Tsuyoshi
T
Takeda
Katsuhiro
K
Uchida
Yuushi
Y
Kawaguchi
Hiroyuki
H
Kitagawa
Masae
M
Takata
Takashi
T
Kurihara
Hidemi
H
D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D003739:Dental Cementum / Q000166:cytology* / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D020813:Receptor, trkB; D051020:bcl-X Protein; C494811:BCL2L1 protein, human