A self-perpetuating cycle of Type H vessel proliferation and T-2 induced inflammation drives KBD pathogenesis

Kashin-Beck disease (KBD) primarily impairs the epiphyseal plate in children and adolescents, resulting in enlarged bone ends and short stature. Given the abundance of type H vessels in the growing epiphyseal plate, this spatiotemporal correlation prompted us to investigate their potential role in KBD.

A rat KBD model was established by feeding T-2 toxin and a low-selenium. Pharmacological modulation of type H vessels was achieved with Roxadustat (promoter) and Halofuginone (inhibitor). Rats were randomly divided into the placebo group (normal), the low-sel + T-2 group (T-2), the low-sel + T-2 + Roxadustat group (T-2 + RD) and the low-sel + T-2 + Halofuginone group (T-2 + HF). Histopathology, immunofluorescence, single-cell RNA sequencing, qPCR, and explants were employed to assess vascular density, T-2 toxin accumulation, inflammatory markers and cartilage integrity.

Roxadustat increased type H vessel density (Mean Difference (MD): 4.11, 95%CI: 0.19, 8.04), amplified T-2 toxin accumulation near the epiphyseal plate (MD: 0.16, 95%CI: 0.062, 0.25) and exacerbated chondrocyte apoptosis and necrosis. Conversely, HF reduced type H vessel proliferation (MD: -3.70, 95%CI: -6.67, -0.73), decreased T-2 toxin levels and suppressed inflammation (MD: -0.17, 95%CI: -0.23, -0.11), while preserving proteoglycan content and cartilage morphology. Single-cell RNA sequencing, qPCR and explants revealed that T-2 toxin-induced inflammation upregulated IL-6 and SELE, promoting type H vessels proliferation.

This study identifies type H vessels as critical mediators of KBD pathogenesis, linking T-2 toxin transport, inflammation and cartilage damage. The findings highlight a vicious cycle involving type H vessel proliferation and inflammatory signaling.