Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development.
In this study, we report that the transcription factor c-Maf is required for normal chondrocyte differentiation during endochondral bone development. c-maf is expressed in hypertrophic chondrocytes during fetal development (E14.5-E18.5), with maximal expression in the tibia occurring at E15.5 and E16.5, in terminally differentiated chondrocytes. In c-maf-null mice, fetal bone length is decreased approximately 10%, and hypertrophic chondrocyte differentiation is perturbed. There is an initial decrease in the number of mature hypertrophic chondrocytes at E15.5 in c-maf-null tibiae, with decreased expression domains of collagen X and osteopontin, markers of hypertrophic and terminal hypertrophic chondrocytes, respectively. By E16.5, there is an expanded domain of late hypertrophic, osteopontin-positive chondrocytes in the c-maf-/-. This accumulation of hypertrophic chondrocytes persists and is still observed at 4 weeks of age. These data suggest that c-Maf facilitates the initial chondrocyte terminal differentiation and influences the disappearance of hypertrophic chondrocytes. BrdU and TUNEL analyses show normal proliferation rate and apoptosis in the c-maf-null. There is a specific decrease in MMP-13 expression at E15.5 in the c-maf-null. MMP-13 is known to be regulated by AP-1 and may also be a target of c-Maf. Thus, cartilage is a novel system in which c-Maf acts during development, where c-Maf is required for normal chondrocyte differentiation.
D000818:Animals; D017209:Apoptosis; D001846:Bone Development / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division; D019902:Chondrocytes / Q000166:cytology*; D017364:Collagenases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D006984:Hypertrophy; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D004268:DNA-Binding Proteins; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D016159:Tumor Suppressor Protein p53; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse