The TNF receptor superfamily: role in immune inflammation and bone formation

Tumor necrosis factor (TNF) and TNF receptor (TNFR) family proteins play important roles in many biological processes. Recently, the TNF-family molecule, RANKL (also called TRANCE, ODF, and OPGL), and its receptors, RANK and OPG, were found to be regulators of the development and activation of osteoclasts in bone remodeling. TNFalphaalso activates osteoclasts both by themselves and in synergy with RANKL. We used structure-based design to create peptidomimetics and organic therapeutics that inhibit osteoclastogenesis by inhibiting the interaction of ligands and receptors. Here we show for the first time that blocking TNFalpha by these small molecules effectively inhibited osteoclast formation in vitro. These mimetics can be used as a probe to understand the molecular basis of osteoclastogenesis and also as a platform to create useful therapeutic agent.