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

Authors

  • J Guicheux,

    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
    2. Research Center on Materials with Biological Interests, Nantes School of Dental Surgery, Nantes, France
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  • J Lemonnier,

    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
    2. Institut National de la santé et de la Recherche Médicale U349, Hôpital Lariboisière, Paris, France
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  • C Ghayor,

    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
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  • A Suzuki,

    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
    2. Division of Endocrinology, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake Aichi, Japan
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  • G Palmer,

    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
    2. Division of Rheumatology, Department of Internal Medicine, University Hospital of Geneva, Geneva, Switzerland
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  • J Caverzasio PhD

    Corresponding author
    1. Division of Bone Diseases, Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland
    • Division of Bone Diseases Department of Geriatrics University Hospital of Geneva CH-1211 Geneva 14, Switzerland
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  • The authors have no conflict of interest.

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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