KCNE3-KCNQ1 ion channel axis orchestrates mitochondrial metabolic reprogramming to couple osteogenesis and angiogenesis in skeletal repair
TL;DR
Findings establish the KCNE3/KCNQ1 axis as a pivotal regulator of skeletal vascular function and mitochondrial energetics during bone repair, highlighting ML277 as a promising therapeutic candidate for fracture nonunion.
Abstract
Recent work has delineated a specialized skeletal vascular subtype, characterized by high expression of CD31 and endomucin (CD31hiEMCNhi), that actively supports bone formation. Nevertheless, the specific contribution of CD31hiEMCNhi endothelium to fracture repair remains largely unresolved. In this study, single‑cell RNA sequencing revealed that KCNE3+ Type H endothelial cells, localized in the epiphysis and periosteum, exhibited strong stemness and drove differentiation into arterial or sinusoidal endothelium. Silencing Kcne3 in bone marrow stromal cells (BMSCs) and human microvascular endothelial cells (HMECs) impaired osteogenic differentiation, angiogenesis, and migration in vitro, accompanied by reduced mitochondrial membrane potential and ATP production. Conditional knockout of Kcne3 in mice (Kcne3cko) resulted in trabecular bone loss, diminished CD31hiEMCNhi vasculature, and defective fracture healing. Mechanistically, fracture healing upregulated potassium ion currents and mitochondrial activity, which were suppressed by Kcne3 knockdown. Rescue experiments demonstrated that activating KCNQ1 channels (a KCNE3-binding partner) with ML277 restored osteogenesis, angiogenesis, and bone mass in Kcne3cko mice. Furthermore, ML277 administration in fracture models enhanced trabecular bone volume and CD31hiEMCNhi endothelial regeneration, accelerating healing. These findings establish the KCNE3/KCNQ1 axis as a pivotal regulator of skeletal vascular function and mitochondrial energetics during bone repair, highlighting ML277 as a promising therapeutic candidate for fracture nonunion.