Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.cbi.2012.12.016
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dc.titleRANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines
dc.contributor.authorNaidu, V.G.M.
dc.contributor.authorDinesh Babu, K.R.
dc.contributor.authorThwin, M.M.
dc.contributor.authorSatish, R.L.
dc.contributor.authorKumar, P.V.
dc.contributor.authorGopalakrishnakone, P.
dc.date.accessioned2014-12-01T06:56:33Z
dc.date.available2014-12-01T06:56:33Z
dc.date.issued2013-04-25
dc.identifier.citationNaidu, V.G.M., Dinesh Babu, K.R., Thwin, M.M., Satish, R.L., Kumar, P.V., Gopalakrishnakone, P. (2013-04-25). RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Chemico-Biological Interactions 203 (2) : 467-479. ScholarBank@NUS Repository. https://doi.org/10.1016/j.cbi.2012.12.016
dc.identifier.issn00092797
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/113622
dc.description.abstractPeptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p < 0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30 mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1016/j.cbi.2012.12.016
dc.sourceScopus
dc.subjectArthritis
dc.subjectNF-κB
dc.subjectOsteoprotegrin
dc.subjectPeptidomimetics
dc.subjectRANK
dc.subjectRANKL
dc.typeArticle
dc.contributor.departmentSURGERY
dc.description.doi10.1016/j.cbi.2012.12.016
dc.description.sourcetitleChemico-Biological Interactions
dc.description.volume203
dc.description.issue2
dc.description.page467-479
dc.description.codenCBINA
dc.identifier.isiut000319235100011
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