Publication

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

Wang, Y., Setroikromo, R., van Merkerk, R., Cool, R. H. & Quax, W. J., Sep-2019, In : Febs Journal. 286, 18, p. 3582-3593 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

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-kappa B 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.

Original languageEnglish
Pages (from-to)3582-3593
Number of pages12
JournalFebs Journal
Volume286
Issue number18
Publication statusPublished - Sep-2019

    Keywords

  • fibrosis, liver, lung, OPG, RANK, KAPPA-B LIGAND, OSTEOPROTEGERIN OPG, CRYSTAL-STRUCTURE, ACTIVATOR, IMMUNE

View graph of relations

Download statistics

No data available

ID: 98624776