Reference - Detail
|Author||Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K.|
|Title||Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix.|
|Journal||J. Bone Miner. Res.|
We screened the small molecule compounds that stimulate osteogenesis by themselves or promote bone morphogenetic protein (BMP)-induced bone formation. We found that a specific inhibitor for MAPK/extracellular signal-regulated kinase kinase (MEK)-1, promoted the early osteoblastic differentiation and mineralization of extracellular matrix (ECM) in C2Cl2 pluripotent mesenchymal cells treated with recombinant human BMP-2 (rhBMP-2) and MC3T3-E1 preosteoblastic cells. ALP activity was synergistically increased by the treatment with a specific MEK-1 inhibitor PD98059 and rhBMP-2 in both cell lines. Twenty-five micromolar PD98059 promoted mineralization of ECM in rhBMP-2-treated C2Cl2 cells and MC3T3-E1 cells. In contrast, PD98059 reduced osteocalcin (OCN) secretion and its transcriptional level in rhBMP-2-treated C2Cl2 cells but increased its secretion and mRNA level in MC3T3-E1 cells. Stable expression of a dominant-negative MEK-1 mutant in C2Cl2 cells represented high ALP activity and low osteocalcin production in the presence of rhBMP-2, while a constitutively active mutant of MEK-1 attenuated both of them. Together, our results indicated that BMP-2-induced mineralization of ECM of pluripotent mesenchymal stem cells and preosteoblastic cells could be controlled by a fine tuning of the MAPK signaling pathway. Further, MEK-1 inhibitors would be useful for the promotion of bone formation, for instance, the treatments for delayed fracture healing or advance of localized osteoporotic change after fracture healing.
|MeSH||Animals Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins / pharmacology* Cell Differentiation / drug effects Cell Line / drug effects Cell Line / metabolism Enzyme Induction / drug effects Enzyme Inhibitors / pharmacology* Extracellular Matrix / drug effects* Extracellular Matrix / metabolism Flavonoids / pharmacology* Genes, Dominant Humans MAP Kinase Kinase 1 MAP Kinase Signaling System / drug effects MAP Kinase Signaling System / physiology* Mesoderm / cytology Mice Minerals / metabolism* Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors* Mitogen-Activated Protein Kinase Kinases / physiology Mitogen-Activated Protein Kinases / antagonists & inhibitors* Mitogen-Activated Protein Kinases / physiology Osteoblasts / cytology Osteoblasts / drug effects* Osteoblasts / metabolism Osteocalcin / biosynthesis Osteocalcin / drug effects Osteocalcin / metabolism Pluripotent Stem Cells / cytology Pluripotent Stem Cells / drug effects* Protein-Serine-Threonine Kinases / antagonists & inhibitors* Protein-Serine-Threonine Kinases / physiology RNA, Messenger / biosynthesis RNA, Messenger / genetics Rats Recombinant Fusion Proteins / pharmacology Recombinant Fusion Proteins / physiology Recombinant Proteins Transcription, Genetic / drug effects Transforming Growth Factor beta* p38 Mitogen-Activated Protein Kinases|
|WOS Category||ENDOCRINOLOGY & METABOLISM|
|Human and Animal Cells|