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Fibrosis is characterized by the progressive alteration of the tissue structure due to the excessive production of extracellular matrix ( ECM ). The signaling system encompassing Receptor Activator of Nuclear factor  NF ‐κB Ligand ( RANKL )/ RANK /Osteoprotegerin ( OPG ) was discovered to play an important role in the regulation of  ECM  formation and degradation in bone tissue. However, whether and how this signaling pathway plays a role in liver or pulmonary  ECM  degradation is unclear up to now. Interestingly, increased decoy receptor  OPG  levels are found in fibrotic tissues. We hypothesize that  RANKL  can stimulate  RANK  on macrophages and initiate the process of  ECM  degradation. This process may be inhibited by highly expressed  OPG  in fibrotic conditions. In this case,  RANKL  mutants that can bind to  RANK  without binding to  OPG  might become promising therapeutic candidates. In this study, we built a structure‐based library containing 44  RANKL  mutants and found that the Q236 residue of  RANKL  is important for  OPG  binding. We show that  RANKL _Q236D can activate  RAW  cells to initiate the process of  ECM  degradation and is able to escape from the obstruction by exogenous  OPG . We propose that the generation of  RANKL  mutants with reduced affinity for  OPG  is a promising strategy for the exploration of new therapeutics against fibrosis.

Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity