A key signaling mechanism driving the coordination of osteocytes, osteoclasts, and osteoblasts is the RANK-RANKL-OPG pathway (Figure ). Preosteoclasts and active osteoclasts express receptor activator of nuclear factor kappa-B (RANK) . RANK binds to its ligand RANKL, a soluble and membrane-bound protein expressed by osteoblastic-lineage cells, such as mesenchymal stem cells, preosteoblasts, and osteocytes . RANK-RANKL binding triggers intracellular cascades, such as the nuclear factor kappa B (NF-κB) pathway, which produces nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a transcription factor that induces osteoclastic genes .