HERPUD1 Regulates T2DM Implant Angiogenesis-Osteogenesis By Accelerating TMBIM6 Ubiquitination

This study aims to explore the regulatory mechanisms of H-type vessel-mediated angiogenesis-osteogenesis coupling in Type 2 diabetes mellitus (T2DM), focusing on the roles of HERPUD1 and TMBIM6 in endothelial progenitor cell (EPC) function under high glucose conditions. Under high glucose conditions, the expression levels of HERPUD1 and TMBIM6 were investigated in endothelial progenitor cells (EPCs). HERPUD1 knockdown (Herpud1 KD ) experiments were conducted to assess its impact on EPC function and H-type vessel expression. The regulatory relationship between HERPUD1 and TMBIM6, including ubiquitination and degradation processes, was examined. Rat models of T2DM were employed to evaluate the effects of Herpud1 KD on implant osseointegration. High glucose conditions significantly increased HERPUD1 expression in EPCs, impairing their function, while TMBIM6 levels decreased. Herpud1 KD rescued these impairments, promoting H-type vessel expression and improving implant osseointegration in T2DM rats. HERPUD1 was found to regulate TMBIM6 by accelerating its ubiquitination and degradation, thereby disrupting EPC angiogenesis and angiogenesis-osteogenesis coupling. The HERPUD1-TMBIM6-Ca 2+ axis plays a critical role in impairing EPC angiogenesis under high glucose conditions, affecting angiogenesis-osteogenesis coupling crucial for bone healing. Targeted therapies focusing on the ER pathway could potentially improve implant success rates in diabetic patients by enhancing H-type vessel function and osseointegration.