Single-cell multi-omics reveals unique regulatory mechanisms that sustains unprecedented elongation rate of bone structure, the deer antler

Abstract Bone growth and regeneration remain clinically important problems in medicine, and understanding the mechanism of rapid bone growth is a key to new therapeutic approaches. Deer antlers represent the fastest-growing bone structure in mammals, undergoing regeneration through endochondral ossification and exhibiting extraordinary elongation rates of up to 2 cm per day, far exceeding human epiphyseal growth plate extension of approximately 2 cm annually. This research aimed to systematically map the cellular and molecular architecture of the antler growth center by integrating single-nucleus RNA sequencing (snRNA-seq), chromatin accessibility profiling (snATAC-seq), and spatial transcriptomics. Our analysis revealed that antler mesenchymal stem cells (AnSCs) drive the proliferation of antler progenitor cells (AnPCs) through paracrine signaling. These rapidly proliferating cells maintain genomic stability and evade oncogenic transformation, while displaying distinct molecular signatures that differentiate them from osteosarcoma. AnSC-derived cells also establish a vascularized niche that supports robust angiogenesis to meet the high metabolic demands essential for rapid antler elongation. Furthermore, antlers utilize a hybrid ossification strategy that combines classical endochondral ossification with the direct transdifferentiation of hypertrophic chondrocytes into osteoblasts via PHEX⁺ intermediates. These findings redefine the key principles of endochondral ossification and offer novel insights for the development of regenerative therapies.