Low-dose γ-radiation inhibits IL-1β-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling.
Bottom Line: Here, we found that LDR, at doses of 0.5-2 centiGray (cGy), inhibited interleukin (IL)-1β-induced chondrocyte destruction without causing side effects, such as cell death and senescence.LDR also inhibited chondrocyte destruction through the catenin pathway induced by epidermal growth factor, phorbol 12-myristate 13-acetate, and retinoic acid.Collectively, these results identify the molecular mechanisms by which LDR suppresses pathophysiological processes and establish LDR as a potentially valuable therapeutic tool for patients with cytokine- or soluble factors-mediated cartilage disorders.
Affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea; Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, Korea.Show MeSH
Related in: MedlinePlus
Mentions: To identify the mechanisms by which LDR modulates chondrocyte phenotype, we examined mitogen-activated protein kinase (MAPK) activation and Akt activation in IL-1β-treated chondrocytes before and after LDR exposure. All MAPK proteins, namely ERK, p38, and JNK, were activated by IL-1β treatment. LDR exposure did not affect IL-1β-induced activation of MAPKs (Fig. 3A), indicating that LDR acts through a MAPK signaling-independent pathway to modulate chondrocyte phenotype. Treatment of chondrocytes with IL-1β induced Akt phosphorylation and subsequently deactivated glycogen synthase kinase 3β (GSK3β), a substrate of Akt (Fig. 3B, top), whereas Triciribine, a specific inhibitor of the Akt signaling pathway, markedly attenuated the IL-1β-induced increase in Akt phosphorylation and thus reactivated GSK3β in chondrocytes (Fig. 3B, bottom). Interestingly, treatment with LY294002, another chemical inhibitor of PI3K/Akt signaling, led to recovery of type II collagen and Sox-9 expression, reduction of COX-2 expression, and inhibition of I-κB degradation in IL-1β-treated chondrocytes (Fig. 3C, top). Consistent with this, LY294002 significantly suppressed NF-κB transcriptional activity, decreasing NF-κB activity by approximately 48% and 68% at 10 and 20 μM, respectively, compared to chondrocytes treated with IL-1β alone (Fig. 3C, bottom). Notably, LY294002 treatment in IL-1β-treated chondrocytes led to downregulation of α-, β-, and γ-catenin protein levels induced by IL-1β (Fig. 3D). These results suggest that Akt activation is critically involved in IL-1β-induced chondrocyte disorders via catenin signaling. Therefore, we examined whether LDR modulates IL-1β-induced Akt activity and found that LDR at both 0.5 and 1 cGy suppressed Akt activation induced by IL-1β in chondrocytes (Fig. 3E). Taken together, our data indicate that LDR acts through blockade of the Akt signaling pathway, but not the MAPK pathway, to mitigate the IL-1β-induced destructive cellular phenotype of chondrocytes.
Affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea; Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, Korea.