Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.190598.
Abstract
Modic type 1 and 2 changes (MC-1 and MC-2) are highly prevalent in individuals with chronic low back pain, yet the cellular and molecular mechanisms underlying vertebral endplate degeneration remain poorly defined. Here, we report that osteoclastogenesis is markedly elevated in MC-1 and MC-2 lesions compared to MC-3, suggesting an active role for osteoclasts in the early stages of degeneration. Using a lumbar spine instability (LSI) mouse model, we demonstrate enhanced osteoclast activity in degenerating endplates. RNA sequencing of mononuclear cells isolated from the endplate and adjacent subchondral bone identifies Gdf15 as a potential upstream regulator of this process. Conditional knockout of Gdf15 in monocytes reduces osteoclast formation, aberrant CD31hiEmcnhi angiogenesis, and pain-associated neurogenesis, ultimately mitigating endplate degeneration and mechanical allodynia. Mechanistically, GDF15 promotes the fusion of preosteoclasts by modulating the expression of Rho-family small GTPases. In a humanized GDF15 knock-in mouse model, therapeutic neutralization of GDF15 leads to a reduction in osteoclast burden, improved endplate structure, and attenuated pain behavior. Together, these findings uncover a previously unrecognized role for GDF15 in driving osteoclast-mediated endplate degeneration and highlight its potential as a therapeutic target for the treatment of endplate-related chronic low back pain.
Authors
Xiaoqun Li, Jinhui Wu, Qingjie Kong, Miao Hu, Yuhong Li, Ziheng Wei, Heng Jiang, Xuhui Zhou, Jun Ma
