# NOX2‐Driven Oxidative Stress Promotes EndMT and Uncouples Angiogenesis–Osteogenesis at the Bone–Implant Interface in Diabetes

## TL;DR

Oxidative stress from NOX2 in diabetes disrupts blood vessel and bone formation at implant sites, but inhibiting NOX2 can restore this process and improve bone integration.

## Contribution

Identifies NOX2-driven oxidative stress as a key mechanism disrupting bone-implant integration in diabetes and shows that targeting NOX2 can restore vascular and bone health.

## Key findings

- Pharmacologic NOX2 inhibition or deletion in diabetic models restores endothelial identity and improves bone formation.
- Transcriptomic analysis reveals that NOX2 inhibition reverses key pathways like TGF-β, NF-κB, and Wnt/Notch.
- Restoring type-H endothelium through NOX2 inhibition improves peri-implant bone volume and histological outcomes.

## Abstract

Diabetes undermines implant integration, yet how the bone–implant interface (BII) can be rationally re‐engineered remains unclear. Here endothelial NOX2–driven oxidative stress is identified as a mechanistic switch that triggers endothelial‐to‐mesenchymal transition (EndMT), depletes type‐H (CD31+EMCN+) vessels, and uncouples angiogenesis from osteogenesis. In a diabetic titanium‐implant model, type‐H endothelium and adjacent osteoprogenitors declined early (≈40% loss at 2 weeks), and peri‐implant bone volume is reduced at 8 weeks (BV/TV 40.98 ± 3.96%). Pharmacologic NOX2 inhibition or endothelial‐specific Nox2 deletion restored endothelial identity, suppressed EndMT and apoptosis, rebuilt type‐H networks, and improved bone formation (BV/TV 53.15 ± 4.97%), yielding higher BV/TV and histological indices. In vitro, on titanium surfaces, NOX2 blockade rescued endothelial proliferation, migration, and adhesion architecture and re‐enabled osteogenesis in EC–OB co‐culture. Bulk RNA‐seq demonstrated pathway reversals (TGF‐β, NF‐κB/MAPK, Wnt/Notch, TNF) and attenuated EC to OB ephrin/plexin edges, consistent with guidance/adhesion rewiring. These findings position NOX2 as an actionable vascular target at the BII and suggest interface‐focused delivery (drug coatings, anti‐EndMT functional surfaces, responsive hydrogels) to re‐establish vessel–bone coupling and strengthen osseointegration in diabetes.

NOX2‐driven oxidative stress disrupts angiogenesis–osteogenesis coupling at the diabetic bone–implant interface. Pharmacologic inhibition and endothelial‐specific NOX2 knockout restore type‐H endothelium, suppress EndMT, and improve osseointegration. Transcriptomics implicate TGF‐β, NF‐κB, MAPK, TNF, and Wnt/Notch pathways, highlighting NOX2 as a druggable node for localized, interface‐targeted therapies in diabetic bone regeneration with clinical promise.