Receptor activator of NF-kB ligand (RANKL) is a critical cytokine for osteoclast differentiation, while its mutants have not been well characterized. A natural mutation in human RANKL at residue M199 was described in patients with osteoclast poor autosomal recessive osteopetrosis. We generated three RANKLmutants using site directed mutagenesis and studied their efficacy on osteoclastic activity. We found that RANKLmutants exhibit a drastically reduced ability to induce osteoclast formation, osteoclastic polarization, bone resorption as well as downstream signaling due to misfolded RANKL. Our results show that M199 is a structurally-sensitive residue representative of a curative motif for next-generation anti-resorptive drugs.
|Award date||14 May 2018|
|Publication status||Unpublished - 2018|