Abstract—The maintenance of skeletal integrity is normally the result of the balance of processes of bone modeling and remodeling mediated by the action of different endogenous and exogenous factors that play a direct action mostly to osteoblasts and osteoclasts. Tumors involving skeleton colonize bone structures directly or secondly through the metastatic process of spreading within the bone (Wiswanathan et al., 2009). Tumor cells can strongly accelerate these processes causing an alteration of remodeling and disrupts the normal physiology of the bone that resulting in different degree of osteolytic and osteoblastic bone lesions. Malignant cells within the bone disrupt the normal bone remodeling process throughout activation of different destructive factors. One of this represented by modification of RANK/RANKL/OPG pathway (Barger et al ., 2007). Is now well understood how the molecular triad represented by receptor activator of NF-kB ligand (RANKL), its receptor RANK and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG) play a direct roles in the formation, function and modulation of osteoclast activity (Boyle et al., 2003), but are not fully understood the nature and the mechanism involved in the formation of multinucleated giant cells in various giant cell-containing lesions enclosed Giant Cell Tumor of bone (GCT B ). Our work was focused to evaluate these expressions in different spontaneous cases of feline GCT .