Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes

• Published in: Development (Cambridge) Vol. 138; no. 2; pp. 359 - 370
• Main Authors: Li, Yuwei, Ahrens, Molly J, Wu, Amy, Liu, Jennifer, Dudley, Andrew T
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 15-01-2011
• Subjects: Animals; Animals, Genetically Modified; Base Sequence; beta Catenin - genetics; beta Catenin - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cell Enlargement; Cell Proliferation; Chick Embryo; Chondrocytes - cytology; Chondrocytes - enzymology; Core Binding Factor Alpha 1 Subunit - metabolism; DNA Primers - genetics; Frizzled Receptors - metabolism; Growth Plate - cytology; Growth Plate - embryology; Growth Plate - enzymology; Mice; Mice, Mutant Strains; Models, Biological; Parathyroid Hormone-Related Protein - metabolism; Signal Transduction
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.052324

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.