Human peripheral osteoclast-precursor-development patterns reveal the significance of RPS17-dependent ribosome synthesis to Ankylosing Spondylitis lesions

Abstract Osteoclast-development patterns and their alterations across Ankylosing Spondylitis (AS) conditions are mysterious, making AS treatment difficult. Our study aims to clarify osteoclast-precursor (OCP) development patterns from monocytes and their variations under AS conditions. We performed single-cell transcriptomics in peripheral blood mononuclear cells (PBMCs) from healthy donors and AS patients in the early, aggravated and remission stages. After monocytic reclustering, OCP-development patterns and the alterations upon AS onset and different outcomes were revealed based on single-cell trajectory. The trajectories revealed two monocyte states with strong OCP features, and AS pathogenesis was characterized by their reduction. Ribosome synthesis was considered the essential function for the development towards OCP-featured states, and this function and its representative molecule, RPS17, showed a decreasing trend with AS onset and outcomes. Histology assessment showed that RPS17 underexpression participated in AS inflammatory osteogenesis and ankylosing destruction. Conditional knockout of RPS17 ameliorated ovariectomy-induced bone loss and enhanced osteoclastogenesis, and RPS17 overexpression improved the phenotype of AS-like mice. Importantly, local injection of RPS17-overexpressed monocytic OCPs markedly ameliorated the joint alterations of AS-like mice without promoting bone loss; this was associated with enhanced osteoclastogenesis adjacent to the articular surface and T-cell-suppressive property in monocytic OCPs. Overall, the evolution of monocytes towards OCP-lineage fate mainly depends on ribosome synthesis, and OCP-development disorder participates in AS lesions due to a reduction in RPS17-dependent ribosome synthesis. Notably, RPS17-overexpressed monocytic OCPs have translational potential in preventing and treating AS peripheral lesions.