title: C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes.
abstract: 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-β (C/EBPβ, 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/EBPβ in chondrocytes. C/EBPβ 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/EBPβ 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-2α (HIF-2α), a functional and genetic regulator of knee OA through promoting endochondral ossification, was identified as a potent and functional inducer of C/EBPβ expression in chondrocytes by the CEBPB promoter assay. Hence, C/EBPβ and RUNX2, with MMP-13 as the target and HIF-2α as the inducer, control cartilage degradation. This molecular network in chondrocytes may represent a therapeutic target for OA.
authors.affiliation: Sensory and Motor System Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. hiratam-tky@umin.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirata
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kugimiya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukai
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yano
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Mabuchi
authors.forename: Bishwa Raj
authors.initials: BR
authors.lastname: Sapkota
authors.forename: Toru
authors.initials: T
authors.lastname: Akune
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Takumi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001846:Bone Development; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000235:genetics; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D050659:Core Binding Factor Alpha 1 Subunit; D053509:Matrix Metalloproteinase 13; D000099162:Endothelial PAS Domain-Containing Protein 1; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; C507079:MMP13 protein, human; C507081:Mmp13 protein, mouse