title: Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 (MMP13) expression in association with transcription factor Runx2 during endochondral ossification.
abstract: Endochondral ossification is temporally and spatially regulated by several critical transcription factors, including Sox9, Runx2, and Runx3. Although the molecular mechanisms that control the late stages of endochondral ossification (e.g. calcification) are physiologically and pathologically important, these precise regulatory mechanisms remain unclear. Here, we demonstrate that Osterix is an essential transcription factor for endochondral ossification that functions downstream of Runx2. The global and conditional Osterix-deficient mice studied here exhibited a defect of cartilage-matrix ossification and matrix vesicle formation. Importantly, Osterix deficiencies caused the arrest of endochondral ossification at the hypertrophic stage. Microarray analysis revealed that matrix metallopeptidase 13 (MMP13) is an important target of Osterix. We also showed that there exists a physical interaction between Osterix and Runx2 and that these proteins function cooperatively to induce MMP13 during chondrocyte differentiation. Most interestingly, the introduction of MMP13 stimulated the calcification of matrices in Osterix-deficient mouse limb bud cells. Our results demonstrated that Osterix was essential to endochondral ossification and revealed that the physical and functional interaction between Osterix and Runx2 were necessary for the induction of MMP13 during endochondral ossification.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan. rikonisi@dent.osaka-u.ac.jp
authors.forename: Riko
authors.initials: R
authors.lastname: Nishimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Hata
authors.forename: Takuma
authors.initials: T
authors.lastname: Matsubara
authors.forename: Shiho
authors.initials: S
authors.lastname: Honma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Wakisaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Go
authors.initials: G
authors.lastname: Shioi
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tsumaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yoneda
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse