Design of a RANK-Mimetic Peptide Inhibitor of Osteoclastogenesis with Enhanced RANKL-Binding Affinity

Hur, Jeonghwan; Ghosh, Ambarnil; Kim, Kabsun; Ta, Hai Minh; Kim, Hyunju; Kim, Nacksung; Hwang, Hye-Yeon; Kim, Kyeong Kyu

doi:10.14348/molcells.2016.2286

Cited by 6 publications

(3 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides binding RANK, OPG is able to interact with TRAIL and induces apoptosis of tumor cells through the cell-surface receptors death receptor 4 (DR4) and DR5 in the TNFRSF family [9]. The binding mode to RANKL was determined from computational docking and molecular dynamics simulations [10,11]. OPG is expressed in vivo by ECs, VSMCs, and osteoblasts.…”

Section: The Opg/rankl/rank/trail System: Structures Localizationmentioning

confidence: 99%

The Role of Osteoprotegerin and Its Ligands in Vascular Function

Rochette

Méloux

Rigal

et al. 2019

IJMS

117

View full text Add to dashboard Cite

The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future.

show abstract

Section: The Opg/rankl/rank/trail System: Structures Localizationmentioning

confidence: 99%

The Role of Osteoprotegerin and Its Ligands in Vascular Function

Rochette

Méloux

Rigal

et al. 2019

IJMS

117

View full text Add to dashboard Cite

show abstract

“…For these reasons, the use of small molecules which are able to target remodeling pathways has been advocated [ 12 ]. To this end, peptides such as the gap-junction protein (connexin 43) mimetic (GAP27) [ 13 ], the RANK-mimetic peptide [ 14 ], the OPG-mimetic peptides [ 15 ], the TNF-[alpha] and the RANKL antagonist peptide [ 16 ], and a TNF receptor loop peptide mimic [ 17 ] have been identified as able to reduce bone resorption and/or promote bone formation.…”

Section: Introductionmentioning

confidence: 99%

Gadolinium Tagged Osteoprotegerin-Mimicking Peptide: A Novel Magnetic Resonance Imaging Biospecific Contrast Agent for the Inhibition of Osteoclastogenesis and Osteoclast Activity

et al. 2018

View full text Add to dashboard Cite

The control of osteoblast/osteoclast cross-talk is crucial in the bone remodelling process and provides a target mechanism in the development of drugs for bone metabolic diseases. Osteoprotegerin is a key molecule in this biosignalling pathway as it inhibits osteoclastogenesis and osteoclast activation to prevent run-away bone resorption. This work reports the synthesis of a known osteoprotegerin peptide analogue, YCEIEFCYLIR (OP3-4), and its tagging with a gadolinium chelate, a standard contrast agent for magnetic resonance imaging. The resulting contrast agent allows the simultaneous imaging and treatment of metabolic bone diseases. The gadolinium-tagged peptide was successfully synthesised, showing unaltered magnetic resonance imaging contrast agent properties, a lack of cytotoxicity, and dose-dependent inhibition of osteoclastogenesis in vitro. These findings pave the way toward the development of biospecific and bioactive contrast agents for the early diagnosis, treatment, and follow up of metabolic bone diseases such as osteoporosis and osteosarcoma.

show abstract

“…Hur et al recently reported the synthesis of a peptide inhibitor with enhanced RANKL affinity for osteoclastogenesis. In their work, they present experimental data along with a computational molecular dynamic and a docking study.…”

Section: Introductionmentioning

confidence: 99%

Unraveling Binding Interactions between Human RANKL and Its Decoy Receptor Osteoprotegerin

2017

View full text Add to dashboard Cite

Recent studies have revealed the importance and the active contribution of the RANKL/OPG/RANK pathway in many bone diseases including different forms of common osteoporosis. In this study, we present an extensive atomistic molecular dynamic study of the OPG/RANKL system. Within the molecular models, we varied the number of OPG molecules bound to the RANKL trimer and carried out a study to determine how the binding affinity of the OPG/RANKL system changes as a function of OPG concentration. The molecular mechanics Poisson-Boltzmann surface area method was used to analyze binding free energies. It is shown that the binding affinity decreases with increasing numbers of OPG molecules. Additionally, conformational changes of RANKL, interactions between the N-terminus outlier module of OPG with RANKL, and residues that play an important role in the binding of OPG to RANKL trimer were investigated. A probable cause for unfavorable binding for a third OPG molecule was found. Along with the currently available experimental studies, this computational study will be valuable for the comprehensive understanding of OPG/RANKL at the atomistic level.

show abstract

Design of a RANK-Mimetic Peptide Inhibitor of Osteoclastogenesis with Enhanced RANKL-Binding Affinity

Cited by 6 publications

References 21 publications

The Role of Osteoprotegerin and Its Ligands in Vascular Function

The Role of Osteoprotegerin and Its Ligands in Vascular Function

Gadolinium Tagged Osteoprotegerin-Mimicking Peptide: A Novel Magnetic Resonance Imaging Biospecific Contrast Agent for the Inhibition of Osteoclastogenesis and Osteoclast Activity

Unraveling Binding Interactions between Human RANKL and Its Decoy Receptor Osteoprotegerin

Contact Info

Product

Resources

About