title: Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification.
abstract: Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte- and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption.
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.forename: Je-Hwang
authors.initials: JH
authors.lastname: Ryu
authors.forename: Jimin
authors.initials: J
authors.lastname: Jeon
authors.forename: Siyoung
authors.initials: S
authors.lastname: Yang
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.forename: Hongryeol
authors.initials: H
authors.lastname: Park
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Woo-Shin
authors.initials: WS
authors.lastname: Kim
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis; D049628:Body Size; D001835:Body Weight; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D020219:Chondrogenesis; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D006984:Hypertrophy; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D010012:Osteogenesis; D053245:RANK Ligand / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2
chemical_list: C501127:Dkk1 protein, mouse; C405060:Dkk2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse