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Published on: March 15, 2018
A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B-RAC1-mediated cytoskeletal remodeling
Zheng Zhang1, Zhengbo Tao1, Weijin Zhang1
1Department of Orthopedics, Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.
Abstract:
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.
Insights
A new drug, E8431, targets the DCSTAMP protein to inhibit cell fusion, offering a potential treatment for osteoporosis by preserving bone mass and reducing bone loss.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- DCSTAMP is a key protein in cell fusion during osteoclastogenesis.
- Inhibiting DCSTAMP could increase bone mass via anabolic and anti-catabolic effects.
- No specific DCSTAMP inhibitors have been identified previously.
Purpose of the Study:
- To identify novel small molecule inhibitors of DCSTAMP.
- To investigate the therapeutic potential of identified inhibitors for osteoporosis.
Main Methods:
- Structure-based virtual screening using AlphaFold predictions.
- In vitro assays to assess preosteoclast fusion and bone resorption.
- In vivo studies using ovariectomy-induced osteoporosis mouse models.
Main Results:
- A novel small molecule, E8431, was identified, selectively targeting DCSTAMP's endoplasmic domain.
- E8431 inhibited preosteoclast fusion, reduced bone resorption, and promoted osteogenic/angiogenic processes.
- A new DCSTAMP-RAP1B signaling pathway was uncovered, and E8431 inhibited this interaction.
- E8431 treatment attenuated ovariectomy-induced bone loss in mice without toxicity.
Conclusions:
- E8431 is a potent DCSTAMP inhibitor with therapeutic potential for osteoporosis.
- Targeting the DCSTAMP-RAP1B interaction offers a novel strategy for osteoporosis treatment.
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