Vascular and Lymphatic Dysregulation via Non-EndoMT Col2a1 Signaling in Bisphosphonate-Related Osteonecrosis of the Jaw

作者：Yixin Shi, Haiyang Sun, Zijian Guo, Xian Liu, Xibo Pei, Jian Wang, Fanyuan Yu, Xingchen Peng, Quan Yuan, Anjali P. Kusumbe, Junyu Chen · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.09.27.678999 · 被引用次数：5 · 研究领域：Bone health and treatments、Cancer Diagnosis and Treatment、Bone Tumor Diagnosis and Treatments

Abstract Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the most severe complications of antiresorptive therapy. Although impaired angiogenesis is commonly observed in BRONJ, the underlying vascular mechanisms remain poorly understood, impeding the development of effective treatments. In this study, we integrated whole-organ tissue-clearing imaging, single-cell transcriptomics, and proteomics to construct a multimodal atlas of the mandibular microenvironment in both mouse and human BRONJ. Our findings revealed gross vascular and lymphatic rarefaction in BRONJ, along with 4 endothelial subtypes uniformly exhibiting aberrant upregulation of Col2a1 . Moreover, fibroblasts and macrophages emerged as key endothelial interactors, collectively underscoring dysregulation of the endothelium-matrix-immune axis. Unlike homeostatic Dmp1 ⁺/ Tfap2a ⁺ fibroblasts and Stab1 ⁺ macrophages, BRONJ lesions featured pathological Lrrc15 ⁺/ Chad ⁺ fibroblasts and Il6 ⁺ macrophages, which promote ectopic chondrogenesis and inflammation. Mechanistically, BRONJ activated the COL2A1-CD44 axis (EC-to-fibroblast/macrophage signaling) and COL2A1-SDC4 axis (EC-to-fibroblast signaling), whereas lineage tracing excluded endothelial-to-mesenchymal transition (EndoMT), implicating extracellular matrix remodeling as the driver of dysfunction. Cross-species validation in human mandibles further confirmed vascular-lymphatic dysregulation, inflammatory activation, and aberrant chondrogenesis. Ov...