TNFRSF11B is a member of the TNFR family, which lacks the transmembrane domain and acts as a secreted decoy receptor with no direct signaling capacity. It plays a key role in the physiological regulation of osteoclastic bone resorption, postnatal bone formation, and pathological calcification of arteries. TNFRSF11B binds to its natural ligand, RANKL (OPGL), which prevents the interaction of RANKL with its receptor, present on osteoclasts, therefore inhibiting osteoclast differentiation, activation, and survival. Overexpression of TNFRSF11B in transgenic mice leads to deep osteoporosis secondary to an almost total lack of osteoclasts. In addition, TNFRSF11B-deficient mice develop early onset osteoporosis and calcification of the aorta and renal arteries, sites which have endogenous TNFRSF11B expression in normal animals. EBF family member, EBF2 activates TNFRSF11B gene transcription in a synergistic manner with Wnt/β-catenin signaling transcription factor LEF1. In addition to RANKL, TNFRSF11B binds and neutralizes the pro-apoptotic actions of TNF-related apoptosis-inducing ligand (TRAIL) expressed by vascular smooth muscle cells (VSMCs) and T cells. Lastly, TNFRSF11B is involved in B cell development and function. High levels of TNFRSF11B have been detected in serum of patients with cardiovascular diseases, diabetes, and chronic renal failure.