Osteocyte Cell-Cell Communication Within and Beyond Bone

Osteocytes form an extensive cellular network and communicate both with neighboring bone cells and with distant organs. Here, we review evidence on which tissues osteocytes communicate with, and the molecular “language” they use. Recent work has expanded osteocyte communication beyond the classical triad of receptor activator of nuclear factor κB ligand, sclerostin, and fibroblast growth factor 23. Within bone, osteocytes coordinate remodeling through direct cell-cell contacts and rapidly released mediators, acting on timescales relevant to mechanotransduction. Beyond bone, osteocytes signal to adipose tissue, muscle, kidney, cartilage, and vasculature. Extracellular vesicles are increasingly implicated as messengers, as their cargo (RNAs and proteins) can influence stem cell lineage allocation and bone–cartilage interactions. Osteocytes may also support vascular function via mitochondria transfer. Osteocytes integrate mechanical and metabolic cues and transmit information through a broader repertoire of signaling molecules than traditionally appreciated. Recognizing the diversity of target cells and mediators will refine concepts of osteocyte-bone and osteocyte-organ crosstalk and highlight mechanisms that could be targeted to reduce skeletal fragility.