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Cell-based assay strategy for identification of motif-specific RANK signaling pathway inhibitors
1Lead Discovery and Profiling, Bristol-Myers Squibb Company, Wallingford, CT 06492, USA. taosheng.chen@bms.com
Abstract:
Osteoclasts, the principal bone-resorbing cells, not only play a pivotal role in skeletal development and maintenance but are also implicated in the pathogenesis of various bone disorders such as postmenopausal osteoporosis, bone erosion in inflammatory conditions, and tumor-induced osteolysis. As a result, several antiresorptive drugs (agents capable of inhibiting osteoclast formation and/or function) have been developed and are widely used to prevent and treat these bone diseases. However, current antiresorptive agents either lack satisfactory efficacy or cause serious side effects in clinical management of these bone disorders. Almost a decade ago, the receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) was identified as an essential factor required for osteoclast formation. RANKL exerts the effect by binding to its receptor RANK on osteoclast precursors. RANKL also has a decoy receptor, osteoprotegerin (OPG), which inhibits RANKL function by competing with RANK for RANKL. The unraveling of the critical role for the RANKL/RANK/OPG system in osteoclast biology provides an unprecedented opportunity to develop more effective antiresorptive drugs. Unfortunately, the agents currently under development, such as OPG, RANK-Fc, and anti-RANKL antibodies, all inherit a serious drawback--lack of specificity, due to the involvement of the RANKL/RANK/OPG system in other biological processes such as immune response and mammary gland development. Thus, future efforts may need to shift to explore RANK signaling pathways as more effective therapeutic targets. Here, we review our current understanding of RANK signaling in osteoclasts and then discuss the potential of RANK signaling pathways as therapeutic pathways. Moreover, we further describe a strategy for constructing novel cell-based systems for identifying compounds inhibiting signaling from two recently identified RANK motifs through high throughput screening. We hope that this review will not only provide readers with an update on progress in this area of research but, more importantly, will also serve as a starting point for further discussion and eventual development of new strategies for harnessing the ultimate potential of the RANKL/RANK/OPG system as antiresorptive therapeutic targets.
Insights
Current antiresorptive drugs for bone disorders lack efficacy and cause side effects. Targeting RANK signaling pathways offers a promising strategy for developing novel, specific therapeutics for bone diseases.
Area of Science:
- Bone biology and therapeutics
- Cell signaling and molecular targets
- Drug discovery and development
Background:
- Osteoclasts are key to bone resorption and implicated in diseases like osteoporosis.
- Existing antiresorptive drugs have limited efficacy and significant side effects.
- The RANKL/RANK/OPG system is crucial for osteoclastogenesis but also involved in other physiological processes.
Purpose of the Study:
- To review the current understanding of RANK signaling in osteoclasts.
- To discuss the therapeutic potential of RANK signaling pathways.
- To present a strategy for identifying novel inhibitors of RANK signaling.
Main Methods:
- Review of existing literature on RANK signaling and osteoclast biology.
- Discussion of therapeutic strategies targeting RANK pathways.
- Description of a novel cell-based high-throughput screening system.
Main Results:
- The RANKL/RANK/OPG system, while vital for osteoclasts, lacks specificity for therapeutic targeting.
- RANK signaling pathways present a more specific target for antiresorptive drug development.
- A novel screening strategy can identify compounds inhibiting specific RANK signaling motifs.
Conclusions:
- Targeting RANK signaling pathways offers a more specific approach to developing effective antiresorptive therapies.
- Novel cell-based screening systems can accelerate the discovery of compounds targeting RANK signaling.
- Further research into RANK signaling is crucial for advancing treatments for bone disorders.
