TY - JOUR
T1 - Inhibition of MEK/ERK upregulates GSH production and increases RANKL-induced osteoclast differentiation in RAW 264.7 cells
AU - Agidigbi, Taiwo Samuel
AU - Kang, In Soon
AU - Kim, Chaekyun
N1 - Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020
Y1 - 2020
N2 - Osteoclasts (OCs) are multinucleated cells that are phylogenetically evolved from monocyte–macrophage lineage and are essential for skeletal coupling processes. During bone development, bone formation by osteoblasts and bone resorption by OCs are tightly coupled and are involved in bone homeostasis. Therefore, it is essential to understand the mechanisms that regulate OC differentiation in order to develop effective therapeutics for the treatment of OC-associated diseases. This study aimed to determine the molecular mechanisms regulating OC differentiation. The mitogen-activated protein kinases and extracellular signal-regulated kinase (ERK) are recognised 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.
AB - Osteoclasts (OCs) are multinucleated cells that are phylogenetically evolved from monocyte–macrophage lineage and are essential for skeletal coupling processes. During bone development, bone formation by osteoblasts and bone resorption by OCs are tightly coupled and are involved in bone homeostasis. Therefore, it is essential to understand the mechanisms that regulate OC differentiation in order to develop effective therapeutics for the treatment of OC-associated diseases. This study aimed to determine the molecular mechanisms regulating OC differentiation. The mitogen-activated protein kinases and extracellular signal-regulated kinase (ERK) are recognised 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.
KW - ERK
KW - PD98059
KW - RANKL
KW - glutathione
KW - osteoclast
UR - http://www.scopus.com/inward/record.url?scp=85082578496&partnerID=8YFLogxK
U2 - 10.1080/10715762.2020.1742896
DO - 10.1080/10715762.2020.1742896
M3 - Article
C2 - 32183593
AN - SCOPUS:85082578496
SN - 1071-5762
VL - 54
SP - 894
EP - 905
JO - Free Radical Research
JF - Free Radical Research
IS - 11-12
ER -