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

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.