C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes

• DOI: 10.1093/hmg/ddr540
• Publication Date: 2011-11-18T01:44:01Z
• Authors: Makoto Hirata; Fumitaka Kugimiya; Atsushi Fukai; Taku Saito; Fumiko Yano; Toshiyuki Ikeda; Akihiko Mabuchi; Bishwa Raj Sapkota; Toru Akune; Nao Nishida; Noriko Yoshimura; Takumi Nakagawa; Katsushi Tokunaga; Kozo Nakamura; Ung-il Chung; Hiroshi Kawaguchi
• Keywords: RUNX2; Endochondral ossification; Inducer

To elucidate the molecular mechanism underlying endochondral ossification process during skeletal growth and osteoarthritis (OA) development, we examined signal network around CCAAT/enhancer-binding protein-β (C/EBPβ, encoded by CEBPB), a potent regulator of this process. Computational predictions C/EBP motif-reporter assay identified RUNX2 as most transcriptional partner C/EBPβ in chondrocytes. were induced co-localized highly differentiated chondrocytes OA development mice humans. The compound knockout Cebpb Runx2 caused retardation resistance to with decreases cartilage degradation matrix metalloproteinase-13 (Mmp-13) expression. cooperatively enhanced promoter activity MMP13 through specific binding C/EBP-binding motif an osteoblast-specific cis-acting element 2 protein complex. Human genetic studies failed show association human CEBPB gene polymorphisms knee OA, nor was there variation responsive region promoter. However, hypoxia-inducible factor-2α (HIF-2α), functional promoting ossification, inducer expression assay. Hence, RUNX2, MMP-13 target HIF-2α inducer, control degradation. This may represent therapeutic for OA.