CD14は、外傷後変形性関節症の複数のモデルにおける疼痛と炎症に重要な役割を果たします

We employed global genetic deletion of CD14 and intra-articular CD14 blockade across multiple murine OA models that vary in severity of pathology and rate of progression, to test the hypothesis that CD14 inhibition attenuates synovial inflammation and associated pain during disease progression.

Human OA synovial fluid samples were evaluated for associations between sCD14 levels with knee hyperalgesia and inflammation. Next, the effect of CD14-deficiency on OA progression was assessed across mild to severe murine surgical models of PTOA, where pain behavior and a high-dimensional transcriptomic and proteomic analysis of CD14-dependent synovial inflammation were performed. In a therapeutic approach, local delivery of a CD14 blocking antibody was administered, and the effects on OA histopathology and pain were evaluated across surgical and nonsurgical murine models of PTOA.

Increased sCD14 within human synovial fluid correlates with joint effusion volume and knee hyperalgesia. Further, targeting CD14 protects from increased evoked pain behaviors and OA-driven mobility impairments across murine models that differ in severity, and across male and female cohorts. Using flow cytometry, single-cell transcriptomics, and spatial proteomics, we further show that CD14-deficiency modulates the synovial and fat pad inflammatory landscape post-injury, reducing myeloid populations and modulating local fibroblast populations. Lastly, across surgical and nonsurgical PTOA models, which incorporated risk factors of sex and obesity, we reveal that local delivery of a CD14 blockade protects against OA-associated pain and mobility loss.

Our results strongly support that targeting synovial and fat pad inflammation through blockade of CD14 can safely ameliorate OA pain and disability after a pre-disposing injury.