title: Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes.
abstract: For tissues that develop throughout embryogenesis and into postnatal life, the generation of differentiated cells to promote tissue growth is at odds with the requirement to maintain the stem cell/progenitor cell population to preserve future growth potential. In the growth plate cartilage, this balance is achieved in part by establishing a proliferative phase that amplifies the number of progenitor cells prior to terminal differentiation into hypertrophic chondrocytes. Here, we show that endogenous calcium/calmodulin-dependent protein kinase II (CamkII, also known as Camk2) activity is upregulated prior to hypertrophy and that loss of CamkII function substantially blocks the transition from proliferation to hypertrophy. Wnt signaling and Pthrp-induced phosphatase activity negatively regulate CamkII activity. Release of this repression results in activation of multiple effector pathways, including Runx2- and β-catenin-dependent pathways. We present an integrated model for the regulation of proliferation potential by CamkII activity that has important implications for studies of growth control and adult progenitor/stem cell populations.
authors.affiliation: Department of Molecular Biosciences, Northwestern University, 2205 Tech Drive, Hogan 2-100, Evanston, Illinois 60208-3500, USA.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Li
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Ahrens
authors.forename: Amy
authors.initials: A
authors.lastname: Wu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Liu
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Dudley
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D049108:Cell Enlargement; D049109:Cell Proliferation; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology* / Q000201:enzymology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D051157:Frizzled Receptors / Q000378:metabolism; D006132:Growth Plate / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D017931:DNA Primers; D051157:Frizzled Receptors; D044162:Parathyroid Hormone-Related Protein; C493716:Runx2 protein, mouse; D051176:beta Catenin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2