Sphingosine-1-phosphate/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation and thereby induces Runx2 expression in osteoblasts

Autor: Yoko Hashimoto, Katsumasa Higashi, Aiko Takano, Fumi Takahashi-Yanaga, Hisashi Anan, Etsuko Matsuzaki, Masato Hirata, Fusanori Nishimura
Rok vydání: 2015
Předmět:
musculoskeletal diseases
0301 basic medicine
Histology
RHOA
Physiology
Endocrinology
Diabetes and Metabolism
Core Binding Factor Alpha 1 Subunit
Smad Proteins
Models
Biological
Cell Line
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Sphingosine
medicine
Animals
Sphingosine-1-phosphate
RNA
Messenger
Phosphorylation
Bone regeneration
Cell Nucleus
rho-Associated Kinases
Osteoblasts
biology
Osteoblast
Cell Differentiation
Alkaline Phosphatase
Cell biology
RUNX2
Mice
Inbred C57BL
Protein Transport
Receptors
Lysosphingolipid
030104 developmental biology
medicine.anatomical_structure
chemistry
Hes3 signaling axis
030220 oncology & carcinogenesis
Cancer research
biology.protein
lipids (amino acids
peptides
and proteins)
Signal transduction
Lysophospholipids
rhoA GTP-Binding Protein
Biomarkers
Signal Transduction
Zdroj: Bone. 93
ISSN: 1873-2763
Popis: Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that also plays crucial roles in bone regeneration. Recently, we reported that the S1P receptors S1PR1 and S1PR2 were mainly expressed in osteoblast-like cells, and that the S1P/S1PR1 signaling pathway up-regulated osteoprotegerin and osteoblast differentiation. However, the involvement of S1P/S1PR2 signaling in osteoblast differentiation is not well understood. Here we investigate the role of S1P/S1PR2-mediated signaling in osteoblast differentiation and clarify the underlying signaling mechanisms. We found that an S1P/S1PR2/Gi-independent signaling pathway activated RhoA activity, leading to phosphorylation of Smad1/5/8 in mouse osteoblast-like MC3T3-E1 cells and primary osteoblasts. Furthermore, this signaling pathway promoted nuclear translocation of Smad4, and increased the amount of Smad6/7 protein in the nucleus. S1P also up-regulated runt-related transcription factor 2 (Runx2) expression through S1PR2/RhoA/ROCK/Smad1/5/8 signaling. Moreover, we found that S1P partially triggered S1PR2/RhoA/ROCK pathway leading to bone formation in vivo. These findings suggest that S1P induces RhoA activity, leading to the phosphorylation of Smad1/5/8, thereby promoting Runx2 expression and differentiation in osteoblasts. Our findings describe novel molecular mechanisms in S1P/S1PR2-mediated osteoblast differentiation that could aid future studies of bone regeneration.
Databáze: OpenAIRE
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