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Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity.
J Biol Chem. 2004 Sep 03; 279(36):37704-15.JB

Abstract

To examine early events in osteoblast differentiation, we analyzed the expression of about 9,400 genes in the murine MC3T3 cell line, whose robust differentiation was documented cytochemically and molecularly. The cells were stimulated for 1 and 3 days with the osteogenic stimulus containing bone morphogenic protein 2. Total RNA was extracted and analyzed by Affymetrix GeneChip oligonucleotide arrays. A regulated expression of 394 known genes and 295 expressed sequence tags was detected. The sensitivity and reliability of detection by microarrays was shown by confirming the expression pattern for 20 genes by radioactive quantitative reverse transcription-PCR. Functional classification of regulated genes was performed, defining the groups of regulated growth factors, receptors, and transcription factors. The most interesting finding was concomitant activation of transforming growth factor-beta, Wnt, and Notch signaling pathways, confirmed by strong up-regulation of their target genes by PCR. The transforming growth factor-beta pathway is activated by stimulated production of the growth factor itself, while the exact mechanism of Wnt and Notch activation remains elusive. We showed that bone morphogenic protein 2 stimulated expression of Hey1, a direct Notch target gene, in mouse MC3T3 and C2C12 cells, in human mesenchymal cells, and in mouse calvaria. Small interfering RNA-mediated inhibition of Hey1 induction led to an increase in osteoblast matrix mineralization, suggesting that Hey1 is a negative regulator of osteoblast maturation. This negative regulation is apparently achieved via interaction with Runx2: Hey1 completely abrogated Runx2 transcriptional activity. These findings identify the Notch-Hey1 pathway as a negative regulator of osteoblast differentiation/maturation, which is a completely novel aspect of osteogenesis and could point to possible new targets for bone anabolic agents.

Authors+Show Affiliations

Arthritis and Bone Metabolism/Gastrointestinal Disease Area, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15178686

Citation

Zamurovic, Natasa, et al. "Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-beta Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis. Notch Target Gene Hey1 Inhibits Mineralization and Runx2 Transcriptional Activity." The Journal of Biological Chemistry, vol. 279, no. 36, 2004, pp. 37704-15.
Zamurovic N, Cappellen D, Rohner D, et al. Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem. 2004;279(36):37704-15.
Zamurovic, N., Cappellen, D., Rohner, D., & Susa, M. (2004). Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. The Journal of Biological Chemistry, 279(36), 37704-15.
Zamurovic N, et al. Coordinated Activation of Notch, Wnt, and Transforming Growth Factor-beta Signaling Pathways in Bone Morphogenic Protein 2-induced Osteogenesis. Notch Target Gene Hey1 Inhibits Mineralization and Runx2 Transcriptional Activity. J Biol Chem. 2004 Sep 3;279(36):37704-15. PubMed PMID: 15178686.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. AU - Zamurovic,Natasa, AU - Cappellen,David, AU - Rohner,Daisy, AU - Susa,Mira, Y1 - 2004/06/02/ PY - 2004/6/5/pubmed PY - 2004/12/16/medline PY - 2004/6/5/entrez SP - 37704 EP - 15 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 36 N2 - To examine early events in osteoblast differentiation, we analyzed the expression of about 9,400 genes in the murine MC3T3 cell line, whose robust differentiation was documented cytochemically and molecularly. The cells were stimulated for 1 and 3 days with the osteogenic stimulus containing bone morphogenic protein 2. Total RNA was extracted and analyzed by Affymetrix GeneChip oligonucleotide arrays. A regulated expression of 394 known genes and 295 expressed sequence tags was detected. The sensitivity and reliability of detection by microarrays was shown by confirming the expression pattern for 20 genes by radioactive quantitative reverse transcription-PCR. Functional classification of regulated genes was performed, defining the groups of regulated growth factors, receptors, and transcription factors. The most interesting finding was concomitant activation of transforming growth factor-beta, Wnt, and Notch signaling pathways, confirmed by strong up-regulation of their target genes by PCR. The transforming growth factor-beta pathway is activated by stimulated production of the growth factor itself, while the exact mechanism of Wnt and Notch activation remains elusive. We showed that bone morphogenic protein 2 stimulated expression of Hey1, a direct Notch target gene, in mouse MC3T3 and C2C12 cells, in human mesenchymal cells, and in mouse calvaria. Small interfering RNA-mediated inhibition of Hey1 induction led to an increase in osteoblast matrix mineralization, suggesting that Hey1 is a negative regulator of osteoblast maturation. This negative regulation is apparently achieved via interaction with Runx2: Hey1 completely abrogated Runx2 transcriptional activity. These findings identify the Notch-Hey1 pathway as a negative regulator of osteoblast differentiation/maturation, which is a completely novel aspect of osteogenesis and could point to possible new targets for bone anabolic agents. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15178686/Coordinated_activation_of_notch_Wnt_and_transforming_growth_factor_beta_signaling_pathways_in_bone_morphogenic_protein_2_induced_osteogenesis__Notch_target_gene_Hey1_inhibits_mineralization_and_Runx2_transcriptional_activity_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15178686 DB - PRIME DP - Unbound Medicine ER -