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Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells.

ABSTRACT: Activation of mitogen-activated protein kinases (MAPKs), their upstream activators MAPK kinases (MAPKKs or MEKs) and induction of MKP-1 (CL100/3CH134) and MKP-3 (Pyst1/rVH6) dual-specificity MAPK phosphatases (MKPs) were studied in the mouse embryonic stem cell line P19 during the 7 day induction of neuronal differentiation triggered by aggregation and retinoic acid. ERK (extracellular signal-regulated kinase), but not JNK (c-Jun N-terminal kinase), was found activated with biphasic kinetics: a first transient phase on days 1 and 2, followed by a second activation that was sustained until the appearance of a neuronal phenotype. MEK activation appeared coincident with ERK activation. Cytosolic MKP-3 was induced in parallel to ERK activation, the induction being dependent on ERK activation, as was shown using the MEK-1 inhibitor PD98059. In contrast, nuclear MKP-1 was transiently elevated at 48 h, coincident with ERK inactivation and independently of ERK activity. As shown by cell fractionation, activated ERK is translocated to the nucleus. The complementary induction of ERK-specific phosphatases MKP-1 and MKP-3 permits precise and independent control of cytoplasmic and nuclear ERK activity, most probably required to properly induce a complex cellular programme of differentiation.

SUBMITTER: Reffas S

PROVIDER: S-EPMC1221507 | biostudies-other | 2000 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundThe objectives of this study was to explore the activation of the extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway and osteogenesis-related factors in the subchondral bone of patients with knee osteoarthritis (OA).MethodsTen patients with primary OA who underwent total knee arthroplasty in the Department of Arthritis Surgery of our hospital were enrolled, and subchondral bone tissue samples were obtained during the operation. He staining and saffron staining were used to observe the arrangement of chondrocytes in the patient tissues. The protein expression levels of JNK, p-JNK, ERK, p-ERK, Runx2 and OMD in subchondral bone were detected by Western Blot. Knee osteoarthritis mice were established. He staining was used to observe the arrangement of subchondral bone cells in the knee joint of mice. Cellular mineralized nodules were determined by alizarin red staining.ResultsFirstly, in general and staining, it was observed that the subchondral bone lesions of knee OA participants were obvious. Compared with normal knee joints, the levels of phosphorylation-c-Jun N-terminal kinase (P-JNK) and phosphorylation-extracellular-signal-regulated kinase (P-ERK) in the subchondral bone of knee arthritis participants were significantly increased (P<0.05). The level of osteomodulin (OMD) was significantly reduced (P<0.05). Secondly, compared with normal mice, the levels of JNK, P-JNK, OMD, ERK, and P-ERK in the model group were significantly different (P<0.05). At 2-8 weeks, the JNK and P-JNK levels in the mice model group increased significantly over time (P<0.05), and the OMD level decreased significantly over time (P<0.05). The levels of ERK and P-ERK fluctuated over time. Thirdly, osteoblasts were treated with different concentrations of anisomycin, and stained with alizarin red after continuous culture for 24 and 48 h, respectively. It was found that all the cells were stained with orange-red mineralized nodules. As the concentration of anisomycin was increased, the number of cell mineralization nodules was significantly larger, and the positive rate of chemical nodules increased. Different concentrations of anisomycin were given to interfere with the osteoblasts of mice. When anisomycin was administered at a dose of 25 ng, the OMD level reached the highest level. When the concentration of anisomycin was increased, the osteocalcin (OCN) level also showed an upward trend.ConclusionsThe process by which the JNK signaling pathway regulates OMD may be closely related to the pathological changes of subchondral bone in patients with knee OA, and is involved in the occurrence and development of knee arthritis.

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Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells.

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