Contrary to what was once thought, osteoclasts are not related to osteoblasts. They are derived from the fusion of mononuclear hemopoietic cells, namely, granulocyte/ macrophage progenitor cells (GMP, CFU-GM) that give rise to granulocyte and monocyte cell lineages (see Fig. 10.16). Osteoclast formation occurs in close association with stromal cells in bone marrow. These cells secrete essential cytokines for differentiation of both osteoclasts and macrophages from GMP progenitor cells, including monocyte colony-stimulating factor (M-CSF), TNF, and several interleukins. Initially, cells committed to become osteoclasts (osteoclast precursors) express two important transcription factors, c-fos and NFB; later, a receptor molecule called receptor activator of nuclear factor  B (RANK) is expressed on their surface. The RANK receptor interacts with RANK ligand molecule (RANKL) produced and expressed on the stromal cell surface (Fig. 8.13). The RANK–RANKL signaling mechanism is essential for osteoclast differentiation and maturation. Alternatively, during inﬂammation, activated T lymphocytes can produce both membrane-bound and soluble RANKL molecules. Therefore, inﬂammatory processes can stimulate osteoclast-mediated bone resorption. This pathway can be blocked by osteoprotegerin (OPG), which serves as a “decoy” receptor for RANKL. Lack of available ligand affects the RANK–RANKL signaling pathway and acts as a potent inhibitor of osteoclast formation. OPG is produced mainly by osteoblasts and is regulated by many bone metabolic regulators, such as IL-1, TNF, TGF, vitamin D, and prostaglandin E2. Recent studies indicate
FIGURE 8.11 • Electron micrograph of bone-lining cells. a. The cytoplasm of a bone-lining cell located on the surface of a spicule of mature bone is very attenuated and contains small amounts of rER and free ribosomes. A gap junction is seen between the two adjacent bone-lining cells. In addition, cytoplasmic processes are clearly seen where they pass through the matrix of unmineralized bone (osteoid). A fat cell of the marrow is also present. 8,900. (Reprinted with permission from Miller SC, Bowman BM, Smith JM, Jee WS. Characterization of endosteal bone-lining cells from fatty marrow bone sites in adult beagles. Anat Rec 1980;198:163–173.) Inset. High-magnification photomicrograph of a similar bone spicule stained with H&E, included for orientation purposes. The bone-lining cells (endosteal cells) on the surface of the spicule are indicated by the arrows. 350. b. Electron micrograph of the cytoplasm of two bone-lining cells observed at higher magnification. The gap junction is clearly seen where the two cells are in apposition. The edge of a fat cell is seen at the top of the electron micrograph; its lipid, thin rim of cytoplasm, plasma membrane, and external lamina are also evident. 27,000.
that substances that promote osteoclast differentiation and bone resorption act through the OPG/RANKL system in the bone marrow. Both OPG and RANKL are detected in a free form in the blood, and their concentrations can be measured for diagnostic purposes and to monitor therapy of many bone diseases.
Newly formed osteoclasts undergo an activation process to become bone-resorbing cells.