Regulation of osteoclasts

Osteoclasts are the cells that resorb both the mineral and matrix components of bone (see Section 6.21.2.2.1). Osteoclasts are derived from hematopoietic cells of the monocyte-macrophage lineage but their recruitment, differentiation, activity, and survival are regulated locally by mesenchymal cells of the osteoblast lineage during normal bone remodeling. The mesenchymal cells provide colony stimulating factor-1 (CSF-1), which is a permissive factor

Figure 4 Osteoclast regulation. Osteoblast lineage cells integrate proresorptive hormonal and paracrine signals and induce bone resorption by producing the TNF family cytokine RANKL, as either a membrane-bound or soluble ligand for its receptor RANK on osteoclasts or their precursors. Ligand binding induces osteoclast differentiation and activation. Conversely, osteoblast lineage cells can secrete the decoy receptor OPG that binds to RANKL and prevents its interaction with RANK, thus inhibiting bone resorption.

Figure 4 Osteoclast regulation. Osteoblast lineage cells integrate proresorptive hormonal and paracrine signals and induce bone resorption by producing the TNF family cytokine RANKL, as either a membrane-bound or soluble ligand for its receptor RANK on osteoclasts or their precursors. Ligand binding induces osteoclast differentiation and activation. Conversely, osteoblast lineage cells can secrete the decoy receptor OPG that binds to RANKL and prevents its interaction with RANK, thus inhibiting bone resorption.

essential for the survival in bone of osteoclast precursors. The importance of colony stimulating factor-1 is shown by the osteopetrotic phenotype of mice lacking this cytokine.16

In addition, osteoblast lineage cells regulate bone resorption by activating another cytokine pathway. This pathway consists of three players: (1) the receptor activator of NFkB (RANK), which is expressed on osteoclasts and their precursors; (2) its ligand RANKL, which is a member of the tumor necrosis factor (TNF) superfamily and expressed by osteoblast precursors; and (3) the decoy receptor for RANKL, osteoprotegerin (OPG), which is also expressed by osteoblast lineage cells (Figure 4). Osteoblast lineage cells integrate multiple systemic and local proresorptive signals and translate net impetus for bone resorption into changes in relative RANKL/OPG expression. The number and activity of osteoclasts are determined by the relative local levels of RANKL and OPG, which promote and inhibit osteoclast differentiation and activity, respectively. Other cells, such as activated T cells, are also able to express RANKL and may contribute to pathologic bone resorption during inflammation.17

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