Vicious cycle in osteolytic bone metastasis. The pro-osteolytic factors secreted by the tumor cells (PTHrP, IL-1, IL-8, IL-11, soluble RANKL, TNF-α, and PGE) promote osteolysis by stimulating osteoclast formation and maturation. The growth factors secreted following osteolysis (BMP, IGF, and TGF-β) are stimulatory for tumor growth, which results in increased tumor burden and eventually more osteolysis. The inset delineates the regulation of osteoclast formation and activation. RANKL on the osteoblast/stromal cells interacts with the RANK on the osteoclast precursors in the presence of M-CSF to stimulate their differentiation into mature osteoclasts. An alternate pathway (RANKL independent) of osteoclast differentiation (mediated by IL-1 and its receptor IL-1R on the osteoclast) is also shown. BMP, bone morphogenetic protein; IGF, insulin-like growth factor; M-CSF, macrophage colony-stimulating factor; OB, osteoblast; OCL, osteoclast; PG, prostaglandin; PTHrP, parathyroid hormone related peptide; IL, interleukin; RANKL, receptor activator of nuclear factor-κB ligand; TGF, transforming growth factor; TNF, tumor necrosis factor.