Receptor activator of nuclear factor kappa B (RANK) pathway for bone metastases

The vicious cycle: osteoblasts are activated by PTHrP, leading to increased production of the receptor activator of nuclear factor kappa B ligand (RANKL). RANKL interacts with RANK receptor expressed on hematopoietic osteoclast precursors, resulting in mature active osteoclasts. Mature osteoclasts resorb bone, causing the release by bone and cancer cells of bone-stored minerals and growth factors, including insulin-like growth factor I (IGF-1), transforming growth factor beta (TGF-beta), interleukin (IL)-6, and more parathyroid hormone releasing protein (PTHrP), thus stimulating tumor cell growth. Osteoprotegerin (OPG) can inhibit this process by binding to RANKL.