Figure 2. Two proposed pathways for osteoclast formation in relation to EARR associated with orthodontic treatment. One pathway is RANK-dependent, while the other one might be mediated by TNFR1 and/or TNFR2 (tumor necrosis factor receptor). RANK is the intrinsic cell-surface determinant that mediates the effects of RANK ligand (RANKL) and osteoprotegerin (OPG) on bone resorption as well as the effects of cytokines like IL-1ß. RANKL (also known as ODF and OPGL), expressed on the surfaces of pre-osteoblastic cells, binds to RANK on the osteoclastic precursor cells and is critical for differentiation, fusion, activation, and survival of osteoclastic cells. OPG (also known as OCIF) puts a brake on the entire system by blocking the effects of RANKL. The pro-resorptive cytokine lL-1ß modulates this system by directly increasing the RANKL expression. Two main components of this pathway (IL-1ß and a marker closely linked to RANK) were found to be in linkage disequilibrium and/or genetically linked to EARR associated with orthodontic treatment. This suggests that osteoclasts stimulated through this pathway are related to root resorption during orthodontic tooth movement. In contrast, TNF in the second pathway is able to induce osteoclast formation in the RANK-independent pathway, presumably by activation of either TNFR1 and/or TNFR2. The absence of association of TNF with EARR in the current study and in previous studies suggests that osteoclastic cells induced through this pathway are not related to root resorption during orthodontic treatment.