Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 5, Pages 1111-1123Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr540
Keywords
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology [19109007, 21390417, 21591930]
- Japanese Orthopaedic Association
- Japan Society for the Promotion of Science (JSPS)
- Grants-in-Aid for Scientific Research [19109007, 22689052, 21591930, 21390417, 23659710] Funding Source: KAKEN
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To elucidate the molecular mechanism underlying the endochondral ossification process during the skeletal growth and osteoarthritis (OA) development, we examined the signal network around CCAAT/enhancer-binding protein- (C/EBP, encoded by CEBPB), a potent regulator of this process. Computational predictions and a C/EBP motif-reporter assay identified RUNX2 as the most potent transcriptional partner of C/EBP in chondrocytes. C/EBP and RUNX2 were induced and co-localized in highly differentiated chondrocytes during the skeletal growth and OA development of mice and humans. The compound knockout of Cebpb and Runx2 in mice caused growth retardation and resistance to OA with decreases in cartilage degradation and matrix metalloproteinase-13 (Mmp-13) expression. C/EBP and RUNX2 cooperatively enhanced promoter activity of MMP13 through specific binding to a C/EBP-binding motif and an osteoblast-specific cis-acting element 2 motif as a protein complex. Human genetic studies failed to show the association of human CEBPB gene polymorphisms with knee OA, nor was there a genetic variation around the identified responsive region in the human MMP13 promoter. However, hypoxia-inducible factor-2 (HIF-2), a functional and genetic regulator of knee OA through promoting endochondral ossification, was identified as a potent and functional inducer of C/EBP expression in chondrocytes by the CEBPB promoter assay. Hence, C/EBP and RUNX2, with MMP-13 as the target and HIF-2 as the inducer, control cartilage degradation. This molecular network in chondrocytes may represent a therapeutic target for OA.
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