Journal Article

A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B–RAC1-mediated cytoskeletal remodeling

Meng, Yichen, Zhang, Zheng, Zhang, Zhanrong, Tao, Zhengbo, Zhou, Xuhui, Xu, Xunpei, Yang, Biao, Zhang, Weijin, Zhang, Xuanrui, Tao, Xia

2025

Overview

DCSTAMP serves as a critical fusogenic protein orchestrating cell–cell fusion during osteoclastogenesis. The disruption of DCSTAMP functionality preserves preosteoclasts, thereby augmenting bone mass through both anabolic and anti-catabolic mechanisms. Despite its therapeutic potential, specific DCSTAMP inhibitors remain undiscovered. Here we used structure-based virtual screening utilizing AlphaFold predictions to identify a novel small molecule, E8431, which selectively targets the endoplasmic domain of DCSTAMP. In vitro investigations confirm E8431’s capacity to impede preosteoclast fusion, concurrently inhibiting bone resorption while stimulating PDGFBB secretion, thus promoting osteogenic and angiogenic processes. We further elucidated a previously uncharacterized DCSTAMP signaling cascade involving DCSTAMP–RAP1B interaction, which activates RAP1–RAC1 signaling-dependent cytoskeletal reorganization. Notably, E8431 demonstrates potent inhibitory effects on this DCSTAMP–RAP1B molecular interface. Moreover, E8431 administration effectively attenuates ovariectomy-induced bone loss in murine models without apparent toxicity, underscoring its potential as a therapeutic agent for osteoporosis. E8431 targets DCSTAMP to enhance bone mass and health This study explores how bone health is maintained and how it can be disrupted, leading to conditions such as osteoporosis. Researchers aimed to find a better treatment by targeting a protein called DCSTAMP, which plays a role in bone cell formation. They used advanced computer models to predict the structure of DCSTAMP and identify potential drugs that could inhibit its function. They tested these drugs in lab experiments and found that E8431 effectively reduced the formation of bone-resorbing cells without harming other cells. E8431 also promote bone formation and blood vessel growth, making it a promising candidate for osteoporosis treatment. E8431 could also offer a new way to treat osteoporosis by addressing multiple aspects of bone health. Future research may focus on refining E8431 for clinical use and exploring its long-term effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/31 / 14/1 / 14/34 / 14/63 / 38/1 / 38/77 / 631/80/128/1276 / 64/60 / 692/699/2743/316/801 / 82/1 / 82/51 / Angiogenesis / Animal models / Animals / Artificial intelligence / Biomedical and Life Sciences / Biomedicine / Bone density / Bone growth / Bone loss / Bone marrow / Bone mass / Bone resorption / Bone Resorption - drug therapy / Bone Resorption - metabolism / Cell Fusion / Cytoskeleton / Cytoskeleton - drug effects / Cytoskeleton - metabolism / Female / Genomes / Humans / Immunohistochemistry / Ligands / Long-term effects / Mathematical models / Medical Biochemistry / Membrane Proteins - antagonists & inhibitors / Membrane Proteins - chemistry / Membrane Proteins - metabolism / Mice / Molecular Medicine / Monoclonal antibodies / Nerve Tissue Proteins / Osteoclastogenesis / Osteoclasts - cytology / Osteoclasts - drug effects / Osteoclasts - metabolism / Osteogenesis / Osteogenesis - drug effects / Osteoporosis / Osteoporosis - drug therapy / Osteoporosis - metabolism / Ovariectomy / Protein Binding / Proteins / rac1 GTP-Binding Protein - metabolism / Rac1 protein / rap GTP-Binding Proteins - metabolism / Rap1 protein / Signal Transduction - drug effects / Stem Cells / Toxicity / 생화학