Signaling Pathways in Osteoclast-driven Bone Metastasis: A mini-review

Abstract

Osteoclasts (OCs), the multinucleated cells derived from the monocyte/macrophage haematopoietic lineage, are responsible degrading bone during skeletal remodeling. OC differentiation, also called osteoclastogenesis, originates from an interaction between the receptor activator of nuclear factor kappa-B ligand (RANKL) and its RANK receptor in OC precursors [1]. Following this interaction, six core signaling cascades including (1) nuclear factor of activated T cells cytoplasmic-1 (NFATc-1); (2) nuclear factor kappa B (NF-κB); (3) phosphatidylinositol 3-kinase (PI3K/Akt); (4) Jun N-terminal kinase (JNK); (5) extracellular signal-regulated kinase (Erk); and (6) p38 mitogen-activated protein kinase (MAPK) are activated, which is prerequisite for OC differentiation [2]. Once formed, mature OCs secrete lytic enzymes such as tartrateresistant acid phosphatase 5 (ACP5/TRAP) [3], Cathepsin K (CTSK) [4] and Metalloproteinases (MMP9 and MMP14) [5] to resorb bone. Besides, binding of monocyte/macrophage colony stimulating factor (MCS-F) to its c-fms receptor is also required for OC survival and differentiation [6].