Disruption of Morrbid alleviates autoinflammatory osteomyelitis in Pstpip2-deficient mice

Autoinflammatory diseases (AIDs) are defined as abnormal activation of the innate immune system leading to spontaneous and uncontrolled inflammation. AIDs may affect bone tissue and lead to chronic recurrent multifocal osteomyelitis (CRMO). However, the etiology and treatment of CRMO remain elusive. In previous studies, we reported that loss of Morrbid prevents myeloid-lineage leukemogenesis. Here, we observed that Morrbid and Pstpip2 are co-expressed in mature myeloid cells and hypothesize a pathogenic role for Morrbid in osteomyelitis. We generated a Pstpip2-/- strain with a 5-bp deletion in Pstpip2, and the strain manifests CRMO-like phenotypes. Loss of Morrbid in Pstpip2-/- mice significantly inhibited the initiation and progression of CRMO symptoms and mitigated activation of myeloid cells and the excessive release of inflammatory cytokines. In addition, single-cell transcriptome analysis demonstrated reduction of osteoclasts and inflammatory cells caused by loss of Morrbid in the Pstpip2-/-Morrbid-/- compound mutants. Using murine models, this study profiles the pathological cell landscape of CRMO by single-cell analysis and suggests that reducing the lifespan of inflammatory myeloid cells by targeting Morrbid can be an effective therapy for chronic osteomyelitis.