title: Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage.
abstract: According to the general understanding, the chondrocyte lineage terminates with the elimination of late hypertrophic cells by apoptosis in the growth plate. However, recent cell tracking studies have shown that murine hypertrophic chondrocytes can survive beyond "terminal" differentiation and give rise to a progeny of osteoblasts participating in endochondral bone formation. The question how chondrocytes convert into osteoblasts, however, remained open. Following the cell fate of hypertrophic chondrocytes by genetic lineage tracing using BACCol10;Cre induced YFP-reporter gene expression we show that a progeny of Col10Cre-reporter labelled osteoprogenitor cells and osteoblasts appears in the primary spongiosa and participates - depending on the developmental stage - substantially in trabecular, endosteal, and cortical bone formation. YFP(+) trabecular and endosteal cells isolated by FACS expressed Col1a1, osteocalcin and runx2, thus confirming their osteogenic phenotype. In searching for transitory cells between hypertrophic chondrocytes and trabecular osteoblasts we identified by confocal microscopy a novel, small YFP(+)Osx(+) cell type with mitotic activity in the lower hypertrophic zone at the chondro-osseous junction. When isolated from growth plates by fractional enzymatic digestion, these cells termed CDOP (chondrocyte-derived osteoprogenitor) cells expressed bone typical genes and differentiated into osteoblasts in vitro. We propose the Col10Cre-labeled CDOP cells mark the initiation point of a second pathway giving rise to endochondral osteoblasts, alternative to perichondrium derived osteoprogenitor cells. These findings add to current concepts of chondrocyte-osteocyte lineages and give new insight into the complex cartilage-bone transition process in the growth plate.
authors.affiliation: Dept. Exp. Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany Department of Pediatrics, Division of Molecular Pediatrics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Jung
authors.initials: J
authors.lastname: Park
authors.affiliation: Dept. Exp. Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gebhardt
authors.affiliation: Dept. Exp. Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Golovchenko
authors.affiliation: Junior Research Group III, Nikolaus-Fiebiger Center of Molecular Medicine, University Hospital, 91054 Erlangen, Germany.
authors.forename: Francesc
authors.initials: F
authors.lastname: Perez-Branguli
authors.affiliation: Dept. of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City,700-8525, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Dept. of Bone- and Skeletal Research, Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Dept. Genetics, MDAnderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Dept. Genetics, MDAnderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: deCrombrugghe
authors.affiliation: Dept. Internal Medicine III, University Hospital Erlangen, D-91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.affiliation: Department of Pediatrics, Division of Molecular Pediatrics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Holm
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Dept. Exp. Medicine I, Nikolaus-Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, 91054 Erlangen, Germany kvdmark@kmolmed.uni-erlangen.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: von der Mark
keywords: Hypertrophic chondrocyte; Osteoprogenitor cell; Trabecular osteoblast; Transdifferentiation