Adrenomedullin from spinal cord injury drives heterotopic ossification in skeletal muscle via a neuro–immune–bone axis

Abstract

Neurological heterotopic ossification can rapidly arise in the periarticular muscles following spinal cord injury. However, the specific mechanism of how the injured central nervous system regulates heterotopic bone formation in peripheral tissues remains largely unexplored. Here we first demonstrate through single-cell RNA sequencing and spatial transcriptomic analysis that fibroadipogenic progenitor cells (FAPs) contribute to heterotopic ossification in injured muscle tissues following spinal cord injury. Mechanistically, we define a neuro–immune–bone axis in which endothelial tip cells within the injured spinal cord serve as a major source of adrenomedullin (ADM), which acts on muscle-resident regulatory T cells (Treg) through RAMP2, promoting their expansion and enhancing their pro-osteogenic phenotype characterized by increased BMP-2 and TGF-β production. These ADM-activated muscle-resident Treg subsequently promote the osteogenic differentiation of FAPs. Conditional knockout of Ramp2 on Treg or inhibition of spinal cord-derived ADM suppresses osteogenic differentiation of FAPs and subsequent neurological heterotopic ossification. Collectively, this work elucidates a mechanistic paradigm in which the injured central nervous system remotely orchestrates peripheral pathology through long-range cellular mediators, redefining our understanding of cross-system communication after neurologic damage. Neurological heterotopic ossification (NHO) is a severe complication following spinal cord injury, where ectopic bone forms in soft tissues, often leading to pain and joint fusion. Current treatments only alleviate symptoms, highlighting a need for deeper understanding of NHO’s pathogenesis. This study explores the mechanisms behind NHO, focusing on the role of fibroadipogenic progenitors and muscle-resident regulatory T cells (Treg). Using spatial transcriptomics and single-cell RNA sequencing, the authors identified a neuro–immune–bone axis where spinal cord-derived adrenomedullin promotes Treg expansion, enhancing their pro-osteogenic phenotype and driving fibroadipogenic progenitors to form bone. The study found that adrenomedullin from endothelial tip cells in the injured spinal cord acts through RAMP2 on Treg, linking spinal cord injury to peripheral ossification. These findings suggest potential therapeutic targets for NHO provide insights into central nervous system control over peripheral tissue homeostasis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.