Cell–Cell Signaling: Broadening Our View of the Basic Multicellular Unit

Abstract

Harold Frost defined the basic multicellular unit (BMU) 50 years ago as the key grouping of cells that achieve structural changes and skeletal renewal by the process of bone remodeling [1]. The BMU includes the bone-resorbing osteoclast, which removes a small quantity of bone, and the bone-forming osteoblast, which replaces the bone removed by osteoclasts. The BMU concept implies the existence of communication pathways between osteoclasts and osteoblasts, between osteoblasts and osteocytes, and among osteoblasts so that bone remodeling can occur in a controlled manner. We now understand that local control of bone remodeling extends beyond the cells of bone proper. Other cell types in the bone marrow influence BMU activity, and these are explored in this issue. Furthermore, we now understand that the influence of the BMU is no longer restricted to bone; factors released from the BMU influence hematopoiesis, kidney function, and glucose metabolism. A full understanding of the interactions within the bone microenvironment will aid with the design of new therapeutic agents for skeletal disorders and should help clinicians using therapies that target osteoclast and osteoblast function. It is for this reason that we have devoted this issue of Calcified Tissue International to expanding our view of the BMU by exploring the full range of paracrine and direct cell-to-cell signals that affect the BMU and its influence on the local environment. We begin with the cells within the bone matrix itself by exploring newly identified roles for the osteocyte and its communication network. Cheung, Kennedy, Majeska, and Schaffler describe this network and the way it senses and responds to changes in the local environment to influence bone structure and systemic phosphate metabolism. Bellido continues the theme, discussing the roles of apoptosis and RANKL/OPG signaling within osteocytes in controlling bone remodeling. Sims and Tonna then address some of the paracrine communication pathways that exist within the osteoblast/osteocyte lineage, including sclerostin, ephrins, and the IL-6 family of cytokines, and their unique roles at different stages of osteogenic differentiation. Two specific cell contact–dependent communication pathways are then detailed. First, Marie, Hay, Modrowski, Revollo, Mbalaviele, and Civitelli review the biologic role of the cadherin family of cell adhesion molecules in controlling osteoblast differentiation and novel approaches for developing new therapies that modify cadherin function. Next, Stains, Watkins, Grimston, Hebert, and Civitelli discuss the role of intercellular communication via gap junctions, focusing on connexin43 and its downstream signals in regulating osteoblast differentiation, function, and survival. Osteoblasts are derived from mesenchymal stem cells, and multiple pathways regulate their lineage commitment. Chen, Lee, and Bae focus on the Notch signaling pathway in osteoblast and chondrocyte development, while Gimble and Nuttall describe the reciprocal relationship between marrow adipocytes and osteoblast generation from their common progenitors and expand this concept to include the effect of adipokines and lipid metabolites on the skeleton. We then move to key interactions on the bone surface that control bone mass. Henriksen, Karsdal, and Martin N. A. Sims (&) Bone Cell Biology and Disease Unit, St. Vincent’s Institute, Melbourne, VIC, Australia e-mail: nsims@svi.edu.au