Intercellular Junctions and Cell–Cell Communication in the Skeletal System

The organization of cells in tissues and organs is controlled by molecular programs that afford cells the ability to recognize other cells and the extracellular matrix and to communicate with their neighbors. Cell–cell and cell–matrix adhesions are mediated by four major groups of molecules: cadherins, immunoglobulin like molecules, integrins, and selectins. This chapter reviews current knowledge about the role of direct cell–cell interactions in the development and remodeling of the skeletal tissue, focusing on cell–cell adhesion via cadherins, cell–cell communication via gap junctions, and short-range calcium signals, or calcium waves, via extracellular nucleotides and purinergic receptors. Cell–cell interactions are critical for aggregation and condensation of immature chondro-osteoprogenitor cells and mesenchymal precursors during skeletal development (bone modeling). This chapter elucidates how interactions with Rho family members provide an inside-out signaling mechanism that regulates cadherin assembly and adhesion properties. By allowing direct interactions among cells of different lineages and by modulating β-catenin signaling, cadherins represent fundamental players in coordinating the activity of cells in the bone marrow microenvironment. Furthermore, two critical steps of osteoclastogenesis, i.e., heterotypic interactions between hematopoietic osteoclast precursors and stromal/osteoblastic cells and osteoclast precursor fusion are both dependent on cell–cell adhesion. Finally, transient and oscillatory elevations of cytosolic free calcium concentrations initiate and modulate a number of cellular activities, including cell growth, motility, and secretion.