Inhibition of MEK/ERK upregulates GSH production and increases RANKL-induced osteoclast differentiation in RAW 264.7 cells.

This study aimed to determine the molecular mechanisms regulating OC differentiation. The mitogen-activated protein kinases and extracellular signal-regulated kinase (ERK) are recognized to be crucial factors regulating OC differentiation and activation. RAW 264.7 cells were differentiated into OCs in the presence of RANKL and were treated with inhibitors of several signal pathways. Although PD98059 is an ERK inhibitor, it inhibited the phosphorylation of ERK, JNK, Akt, and Src kinase. PD98059 increased OC differentiation and expression of OC markers, such as TRAP, calcitonin receptor, and cathepsin K, and increased the expression of NFATc1. Moreover, it also increased the expression of glutamate-cysteine ligase and production of glutathione (GSH). Thus, we examined the involvement of GSH in OC differentiation and observed that GSH treatment alone increased the OC numbers and cotreatment with PD98059 further enhanced OC differentiation. Our results suggested that inhibition of the ERK pathway may promote OC differentiation via upregulation of GSH. These findings reveal that ERK and GSH modulate the signal pathway necessary for OC differentiation, and this may form the basis of a new therapeutic strategy for treating OC-related diseases. PMID: 32183593 [PubMed - as supplied by publisher]
Source: Free Radical Research - Category: Research Tags: Free Radic Res Source Type: research
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