title: Sox9 family members negatively regulate maturation and calcification of chondrocytes through up-regulation of parathyroid hormone-related protein.
abstract: Sox9 is a transcription factor that plays an essential role in chondrogenesis and has been proposed to inhibit the late stages of endochondral ossification. However, the molecular mechanisms underlying the regulation of chondrocyte maturation and calcification by Sox9 remain unknown. In this study, we attempted to clarify roles of Sox9 in the late stages of chondrocyte differentiation. We found that overexpression of Sox9 alone or Sox9 together with Sox5 and Sox6 (Sox5/6/9) inhibited the maturation and calcification of murine primary chondrocytes and up-regulated parathyroid hormone-related protein (PTHrP) expression in primary chondrocytes and the mesenchymal cell line C3H10T1/2. Sox5/6/9 stimulated the early stages of chondrocyte proliferation and development. In contrast, Sox5/6/9 inhibited maturation and calcification of chondrocytes in organ culture. The inhibitory effects of Sox5/6/9 were rescued by treating with anti-PTHrP antibody. Moreover, Sox5/6/9 bound to the promoter region of the PTHrP gene and up-regulated PTHrP gene promoter activity. Interestingly, we also found that the Sox9 family members functionally collaborated with Ihh/Gli2 signaling to regulate PTHrP expression and chondrocyte differentiation. Our results provide novel evidence that Sox9 family members mediate endochondral ossification by up-regulating PTHrP expression in association with Ihh/Gli2 signaling.
authors.affiliation: Department of Molecular and Cellular Biology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Amano
authors.forename: Kenji
authors.initials: K
authors.lastname: Hata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takigawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Makoto
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Kogo
authors.forename: Riko
authors.initials: R
authors.lastname: Nishimura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D020219:Chondrogenesis / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D046509:Tissue Culture Techniques; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D044162:Parathyroid Hormone-Related Protein; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; D000075746:Zinc Finger Protein Gli2