Figure 2. Osteoclasts are derived from hematopoietic stem cells. The osteoclast progenitor cells are closely related to the monocyte/macrophage progenitor cells. Osteoclastogenesis requires initial expansion of the number of progenitor cells induced by activation of c-fms, the receptor for M-CSF. The commitment to the osteoclastic lineage is dependent on activation of the receptor RANK, which is activated by RANKL expressed by stromal cells in bone marrow and osteoblasts in the periosteum. RANK activation results in differentiation of the mononuclear progenitor cells and subsequent fusion to multinucleated latent osteoclasts. Activation of RANK in these cells is required for polarization and activation to mature bone-resorbing osteoclasts. The activation of RANK by RANKL can be inhibited by the RANK-related soluble receptor OPG, released by stromal cells/osteoblasts. Thus, the relative expression of RANKL/OPG is rate-limiting for the osteoclastogenic process. The expression of these molecules is controlled by a variety of hormones and cytokines stimulating bone resorption, e.g., PTH, D3, the IL-6 family of cytokines. Stimulators like PTH and D3 are particularly effective for bone resorption, since activation of their receptors leads to increased RANKL and decreased OPG, whereas members of the IL-6 family of cytokines are less effective, since both RANKL and OPG expression are induced by their receptors.