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PMID:21239498

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Citation

Hisa, I, Inoue, Y, Hendy, GN, Canaff, L, Kitazawa, R, Kitazawa, S, Komori, T, Sugimoto, T, Seino, S and Kaji, H (2011) Parathyroid hormone-responsive Smad3-related factor, Tmem119, promotes osteoblast differentiation and interacts with the bone morphogenetic protein-Runx2 pathway. J. Biol. Chem. 286:9787-96

Abstract

The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3-E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-β. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and β-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts.

Links

PubMed PMC3058974 Online version:10.1074/jbc.M110.179127

Keywords

Alkaline Phosphatase/genetics; Alkaline Phosphatase/metabolism; Animals; Bone Morphogenetic Protein 2/genetics; Bone Morphogenetic Protein 2/metabolism; Cell Differentiation/drug effects; Cell Differentiation/physiology; Cell Line; Core Binding Factor Alpha 1 Subunit/genetics; Core Binding Factor Alpha 1 Subunit/metabolism; Humans; MAP Kinase Signaling System; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mitogen-Activated Protein Kinase 3/genetics; Mitogen-Activated Protein Kinase 3/metabolism; Osteoblasts/cytology; Osteoblasts/metabolism; Osteocalcin/genetics; Osteocalcin/metabolism; Parathyroid Hormone/metabolism; Parathyroid Hormone/pharmacology; Smad1 Protein/genetics; Smad1 Protein/metabolism; Smad3 Protein/genetics; Smad3 Protein/metabolism; Smad5 Protein/genetics; Smad5 Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SMAD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8R138

F

Seeded From UniProt

complete

MOUSE:SMAD5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8R138

F

Seeded From UniProt

complete

MOUSE:RUNX2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8R138

F

Seeded From UniProt

complete

MOUSE:TM119

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P70340
PR:P97454
PR:Q08775

F

Seeded From UniProt

complete

MOUSE:TM119

acts_upstream_of_or_within

GO:0001649: osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TM119

acts_upstream_of_or_within

GO:0001649: osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TM119

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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