MSC polarization in the microenvironment promotes pathological new bone formation in inflammatory lesions

Chronic inflammatory diseases such as ankylosing spondylitis (AS) are characterised by pathological new bone formation (NBF); however, the underlying mechanisms are not well understood. This study investigates the role of mesenchymal stromal cell (MSC) polarization in promoting NBF in the inflammatory microenvironment of AS. Using in vitro and in vivo models, we demonstrate that high levels of interleukin-17 (IL-17) induce the polarization of Toll-like receptor 3-positive (TLR3+) MSC2, driving osteogenic differentiation via the WNT10b pathway. In contrast, low IL-17 levels promote the polarization of TLR4+MSC1, thereby enhancing pro-inflammatory responses. In a decorin-induced mouse model of AS, the implantation of TLR3+MSC2 suppressed local inflammation and promoted NBF. However, TLR3 knockout attenuated these effects. RNA sequencing and functional assays in peripheral blood mononuclear cells (PBMCs) confirmed an association between TLR3+MSC2 polarization and Wnt pathway activation in AS patients with NBF. Furthermore, treatment with TLR4+MSC1 or Wnt inhibitors restored the balance of inflammation and immunity, effectively suppressing pathological NBF. These findings reveal that IL-17-dependent MSC polarization plays a crucial role in regulating the transition from inflammation to NBF in AS via the TLR3/WNT10b axis. This provides new insights into targeted therapies for chronic inflammatory and proliferative disorders.