GPNMB+ macrophages promote osteogenic differentiation of nucleus pulposus cells through PDGF signaling in intervertebral disc degeneration.

Phenotypic transitions of nucleus pulposus (NP) cells are increasingly recognized as key drivers of intervertebral disc degeneration (IVDD), yet the differentiation fate of NP cells and its regulation by the immune microenvironment remain unclear. Using single-cell transcriptomic profiling with in vivo and in vitro validation, we identify an osteoblast-like NP cell subpopulation that emerges during IVDD and exhibits enhanced osteogenic differentiation capacity. Genetic disruption of NP cell osteogenic potential attenuates disc degeneration, supporting a causal role for this program in disease progression. We further show that GPNMB+ macrophages promote osteogenic differentiation and degeneration of NP cells through PDGF signaling and that inhibition of PDGF signaling reduces NP cell osteogenic reprogramming and alleviates disc degeneration. Together, these findings define immune-driven osteogenic reprogramming of NP cells as a key pathological mechanism in IVDD and highlight NP cell osteogenic differentiation as a potential therapeutic target.