CD248/Endosialin regulates synovial fibroblast state to control coupling of inflammation and bone damage in murine models of immune-mediated inflammatory arthritis and ageing.

Objective

Synovial fibroblasts directly contribute to inflammation and damage in immune-mediated inflammatory arthritis. CD248/Endosialin is expressed by fibroblasts in the synovium, is highly upregulated during inflammation and has been proposed as a potential therapeutic target. This study aimed to map the expression of CD248 in disease-associated fibroblast states and to elucidate its role in pathology.

Methods

Molecular profiling of stromal cells from healthy and arthritic (K/BxN serum transfer-induced arthritis) wildtype (Cd248+/+) and Cd248-/- mice was performed using 3' single cell RNA sequencing. Arthritis trajectory and severity were assessed in both genotypes by clinical scoring, microcomputed tomography (microCT), histology and flow cytometry of dissociated synovium. Additionally, healthy mice of each genotype were aged to 20 months and hind limbs assessed by microCT and histology.

Results

Cells expressing high levels of Cd248 also express the 'Pi16' fibroblast progenitor gene signature. Genetic deletion of Cd248 in mice altered the differentiation trajectory of these progenitors, predisposing them to become destructive lining layer fibroblasts. Consequently, Cd248-/- arthritic mice showed a phenotype of rapid, extensive bone damage. Unexpectedly, bone erosion and resultant deformity was also observed in aged Cd248-/- mice in the absence of an inflammatory stimulus.

Conclusion

Genetic deletion of Cd248-/- results in uncoupling of inflammation and damage due to dysregulated fibroblast progenitor differentiation. Our data suggests that the high levels of CD248 expression seen on synovial fibroblasts provides a protective brake that attenuates bone damage by preventing the polarisation of emergent fibroblasts towards a destructive phenotype. Therapeutic targeting of this protein may exacerbate disease.