title: Discoidin domain receptor 2 (DDR2) regulates proliferation of endochondral cells in mice.
abstract: Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens. DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. The decrement of endogenous DDR2 represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells, but the functions of DDR2 in chondrogenic cellular proliferation remain unclear. To better understand the role of DDR2 signaling in cellular proliferation in endochondral ossification, we inhibited Ddr2 expression via the inhibitory effect of miRNA on Ddr2 mRNA (miDdr2) and analyzed the cellular proliferation and differentiation in the prechondrocyte ATDC5 cell lines. To investigate DDR2's molecular role in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of truncated, kinase dead (KD) DDR2 protein is induced, and evaluated the DDR2 function in cellular proliferation in chondrocytes. Although the miDdr2-transfected ATDC5 cell lines retained normal differentiation ability, DDR2 reduction finally promoted cellular proliferation in proportion to the decreasing ratio of Ddr2 expression, and it also promoted earlier differentiation to cartilage cells by insulin induction. The layer of hypertrophic chondrocytes in KD Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates. Taken together, our data demonstrated that DDR2 might play a local and essential role in the proliferation of chondrocytes.
authors.affiliation: Laboratory of Applied Genetics, Graduate School of Agricultural and Life Science, University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Kawai
authors.forename: Tomoka
authors.initials: T
authors.lastname: Hisaki
authors.forename: Koji
authors.initials: K
authors.lastname: Sugiura
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Naito
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kano
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D000070818:Discoidin Domain Receptors; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011975:Receptors, Mitogen / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D011975:Receptors, Mitogen; C493716:Runx2 protein, mouse; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases