Activation of p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase by BMP-2 and Their Implication in the Stimulation of Osteoblastic Cell Differentiation

J. Guicheux, J. Lemonnier, C. Ghayor, Atsushi Suzuki, G. Palmer, Joseph Caverzasio

Research output: Contribution to journalArticle

231 Citations (Scopus)

Abstract

Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression. Introduction: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-β signaling. Materials and Methods: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors. Results: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level. Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.

Original languageEnglish
Pages (from-to)2060-2068
Number of pages9
JournalJournal of Bone and Mineral Research
Volume18
Issue number11
DOIs
Publication statusPublished - 01-11-2003

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Bone Morphogenetic Protein 2
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Cell Differentiation
Osteocalcin
Mitogen-Activated Protein Kinases
Alkaline Phosphatase
Extracellular Signal-Regulated MAP Kinases
Protein Kinase Inhibitors
Heat-Shock Proteins
Immunoprecipitation
Skull
Protein Kinases
Phosphotransferases
Western Blotting

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

@article{ef97ea7b78e14e08a5814d5e197ecdbc,
title = "Activation of p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase by BMP-2 and Their Implication in the Stimulation of Osteoblastic Cell Differentiation",
abstract = "Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression. Introduction: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-β signaling. Materials and Methods: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors. Results: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level. Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.",
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Activation of p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase by BMP-2 and Their Implication in the Stimulation of Osteoblastic Cell Differentiation. / Guicheux, J.; Lemonnier, J.; Ghayor, C.; Suzuki, Atsushi; Palmer, G.; Caverzasio, Joseph.

In: Journal of Bone and Mineral Research, Vol. 18, No. 11, 01.11.2003, p. 2060-2068.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase by BMP-2 and Their Implication in the Stimulation of Osteoblastic Cell Differentiation

AU - Guicheux, J.

AU - Lemonnier, J.

AU - Ghayor, C.

AU - Suzuki, Atsushi

AU - Palmer, G.

AU - Caverzasio, Joseph

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression. Introduction: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-β signaling. Materials and Methods: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors. Results: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level. Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.

AB - Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP-2-induced osteoblastic cell differentiation. We report that BMP-2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression. Introduction: Bone morphogenetic protein (BMP)-2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress-activated protein kinase (SAPK) p38 and c-Jun-NH2-terminal kinase (JNK) pathways have recently been observed in TGF-β signaling. Materials and Methods: Activation of mitogen-activated protein (MAP) kinases by BMP-2 and the role of these signaling pathways for cell differentiation induced by BMP-2 was investigated in mouse MC3T3-E1 and primary cultured calvaria-derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors. Results: Associated with the rapid activation of Smads, BMP-2 barely affected extracellular-signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP-2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP-2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP-2-induced osteoblastic cell differentiation at a transcriptional level. Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP-2-induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.

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