RRC ID 61909
Author Hirao M, Tamai N, Tsumaki N, Yoshikawa H, Myoui A.
Title Oxygen tension regulates chondrocyte differentiation and function during endochondral ossification.
Journal J Biol Chem
Abstract Cartilage functions at a lower oxygen tension than most other tissues. To determine the role of oxygen tension in chondrocyte differentiation and function, we investigated the influence of oxygen tension in the pluripotent mesenchymal cell line C3H10T1/2 and 14.5E mice embryo forelimb organ culture. 10T1/2 cells and embryo forelimbs were cultured under normoxia (20% O2) or hypoxia (5% O2) in the presence of recombinant human bone morphogenetic protein 2. To elucidate the mechanism by which oxygen tension influences chondrocyte differentiation, the Smad pathway was examined using Smad6 overexpression adenovirus and Smad6 transgenic mice embryo forelimbs. The p38 MAPK pathway was examined using dominant-negative MKK3 and FR167653, a specific p38 MAPK inhibitor. The transcriptional activities of Sox9 and Runx2 were also investigated. Hypoxia promoted bone morphogenetic protein 2-induced glycosaminoglycan production and suppressed alkaline phosphatase activity and mineralization of C3H10T1/2. Thus, hypoxia promoted chondrocytic commitment rather than osteoblastic differentiation. In the mice embryo forelimb organ culture, hypoxia increased cartilaginous matrix synthesis. These effects were primarily mediated by p38 MAPK activation, independent of Sox9. Hypoxia inhibited Col10a1 (type X collagen alpha1) expression via down-regulation of Runx2 activity by Smad suppression and histone deacetylase 4 activation. In conclusion, hypoxia promotes chondrocytic differentiation and cartilage matrix synthesis and suppresses terminal chondrocyte differentiation. These hypoxia-induced phenomena may act on chondrocytes to enhance and preserve their phenotype and function during chondrocyte differentiation and endochondral ossification.
Volume 281(41)
Pages 31079-92
Published 2006-10-13
DOI 10.1074/jbc.M602296200
PII S0021-9258(19)89322-5
PMID 16905540
MeSH Animals Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins / metabolism Cartilage / metabolism* Cell Differentiation Chondrocytes / cytology* Gene Expression Regulation* Humans Hypoxia Mice Mice, Inbred C3H Oxygen / metabolism* Recombinant Proteins / metabolism Smad6 Protein / metabolism Transforming Growth Factor beta / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
IF 4.238
Human and Animal Cells 10T1/2(RCB0247)