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Figure 2. Mineralized extracellular matrix in bone is covered by a non-mineralized extracellular matrix (osteoid) produced by osteoblasts, which form a one-cell layer covering all bone surfaces (A). Bone resorption is initiated by hormones, cytokines, or unknown molecules activating receptors present on osteoblasts, which leads to degradation of the osteoid (B) and increased expression of M-CSF and RANKL (C). M-CSF activates its cognate receptor c-fms on osteoclast progenitor cells, which results in proliferation and increased survival, and RANKL activates the receptor RANK, also on osteoclast progenitor cells, resulting in differentiation of these cells along the osteoclastic lineage (D). For osteoclast differentiation to occur, the immunoreceptor tyrosine-based activation motifs harboring molecules FcR
and DAP12 need to be activated by hitherto-unknown ligands (D). The differentiation of the mononuclear osteoclast progenitor cells ends up with fusion to latent multi-nucleated osteoclasts (E), which finally become activated to bone-resorbing osteoclasts (F). The osteoclasts will attach to mineralized bone surface when the osteoblasts have retracted from the area to be resorbed (F).
