Human TRANCE gene, also known as RANKL, encodes a type II membrane protein of 317 amino acids with a predicted molecular mass of 35.4 kD. RANKL is cleaved to produce a soluble form with biological activity. The shedding of membrane-bound RANKL appears to be mediated by expression of matrix metalloproteinase 14 (MMP14) and ADAM10. Suppression of MMP14 in primary osteoblasts increased membrane-bound RANKL and promoted osteoclastogenesis in cocultures with macrophages. Therefore, RANKL shedding seems to be an important process that downregulates local osteoclastogenesis. Conversely, increased production of RANKL by osteoblastic cells leads to osteoclast differentiation, activation, and survival, which results in increased bone resorption. Binding of RANKL to its receptor RANK activates TNF receptor-associated factor 6 (TRAF6), which is linked to downstream pathways including NF-κB, c-jun N-terminal kinase (JNK), and Src. TRAF6 in particular has been shown to be necessary for the differentiation of osteoclastic cells by enhancing Src kinase, essential for osteoclast function. Activation of JNK and NF-κB by RANKL induces the expression of IL-1, IL-6, IL-12, and IL-15 in dendritic cells. In addition, RANKL stimulates proliferation, adhesion, and IL-7 expression of thymic epithelial cells. RANKL can mediate bone loss in arthritis and periodontal disease.