The effect of stress proteins that induce proinflammatory cytokines on pathological root resorption.

本研究以破骨细胞前体细胞（单核/巨噬细胞）作为牙根吸收的体外模型，探讨应激蛋白对破骨细胞（破牙细胞）分化的影响。当用100μg/ml重组人HSP 70和HSP 90刺激细胞时，不诱导促炎细胞因子（IL-1 β、IL-6、TNF-α），并且不影响破骨细胞的分化。根吸收被认为是由破牙细胞诱导的，破牙细胞是在成骨细胞上表达的RANKL（核因子κ B配体的受体激活剂）的刺激下从前体造血干细胞分化而来的。已知RANKL的刺激可诱导信号转导分子MAPK（促分裂原活化蛋白激酶）（包括p38 MARK和ERK（细胞外信号调节激酶））的磷酸化。然后用应激蛋白刺激细胞，以研究应激蛋白是否调节这些信号转导分子的磷酸化。然而，在应激蛋白的刺激下，观察到磷酸化的任何变化。结论：HSP 70和HSP 90不诱导单核/巨噬细胞产生促炎细胞因子，也不影响破骨细胞的分化。然而，在本研究中，发现一个信号转导通路（MEK/ERK）在破骨细胞分化中起着非常重要的作用。MEK抑制剂能显著诱导破骨细胞前体细胞分化，这是首次报道抑制信号转导促进破骨细胞生成。

The effect of stress proteins on osteoclast (odontoclast) differentiation of preosteoclast cells (monocyte/macrophage) which was used as a in vitro model experiment of root resorption in this study. When the cells were stumulated with 100μg/ml recombinant human HSP70 and HSP90, proinflammatory cytokines (IL-1 beta, IL-6, TNF-alpha) were not induced as well as that the osteoclast differentiation was not affected. Root resorption is thought to be induced by odontoclast that is differentiated from precursor hematopeetic stem cells with the stimulation of RANKL (Receptor Activator of Nuclear Flactor kappa B Ligand) expressed on osteoblasts. Stimulation of RANKL is known to induce phospholylation of signal transduction molecules, MAPK (Mitogen Activated Ptotein Kinase) including p38 MARK and ERK (Extracellular ignal-Regulated Kinase). Then the cells were stimulated with stress proteins to investigate if the stress proteins modulate the phosphorylation of those signal transduction molecules. However, any change of phosphorylation was observed with the stimulation of stress proteins. We concluded that HSP70 and HSP90 do no induce proinflammatory cytokines in monocyte/macrophage and do not affect the osteoclast differentiation. However during in this study, a signal trasnduction pathway (MEK/ERK) was found to be very important in osteoclast differentiation. The inhibitors of MEK markedly induced osteoclast differentiation in precursor cell line, which is the first report of the inhibition of signal transduction stimulates osteoclastogenesis.