Intercellular cross-talk among bone cells: new factors and pathways

Intercellular communication within the bone microenvironment is critical for the maintenance of normal bone structure. Osteoblast-lineage cells at all stages of differentiation, from pluripotent precursors to matrix-embedded osteocytes, produce regulatory factors that modulate the differentiation and activity of both bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoclasts can also release factors that feed back to regulate osteoblast activity. Intercellular cross-talk within the bone microenvironment is not restricted only to these bone cells. Other cells within the bone marrow microenvironment, including adipocytes, T cells, and macrophages, play key roles that influence the processes of bone formation and resorption. This review discusses recent work that provides new insights into some of these communication networks and the factors involved, including osteocytic production of receptor activator of nuclear factor-κB ligand (RANKL) and sclerostin, osteoblastic production of interleukin-33, osteoclast-derived Semaphorin 4D, ephrin signaling, and signals from T helper cells and resident osteal macrophages (osteomacs).