The cellular origin of synovial osteoclasts in inflammatory arthritis
Azadi, Kian Armand McCollum
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Inflammatory arthritis (IA) is a debilitating disease that is characterized by joint destruction. This destruction is caused by osteoclasts (OCLs) degrading bone within the synovium, however the exact cellular origins of these synovial OCLs is not well understood. We hypothesize that the synovial OCLs seen in IA are independently derived from two contributing cell lineages: the canonical source of OCL which are Hematopoietic Stem Cell (HSC) derived monocytes and the newly described Erythro-Myeloid Progenitor (EMP). To explore the contribution of these two lineages to synovial OCL, we used Cx3cr1CreERT2;Rosa26LSL-tdTomato mice to label EMP-derived cells, and Flt3Cre;Rosa26LSL-YFP to label HSC-derived cells. Using immunofluorescent histology, we found that synovial OCLs formed under arthritic conditions derive from both HSC and EMP-progenitors, suggesting the possibility that regulatory mechanisms unique to each developmental lineage promote OCL differentiation in arthritic joints. In support of these observations, in IA we detected two populations of mononuclear cells, as possible osteoclast precursors, that express both the OCL marker TRAP and the monocytic/macrophage marker CD68. These mononuclear TRAP+ CD68+ cell populations are found within the inflamed synovium and in bone periosteal surfaces of arthritic joints, and are mostly EMP derived, however, the HSC lineage significantly contributes to osteoclast formation, as suggested by our lineage-tracing strategy. We are currently investigating the dynamics of these cell populations during the early, peak, and resolution stages in an acute murine model of IA. To better understand regulatory differences between OCL derived from each of these lineages, we plan to isolate EMP- and HSC-derived OCLs directly from joints to study their precise phenotype, cytokine differentiation requirements, resorptive capacity and transcriptional activity, by flow cytometry, in vitro cell cultures and single cell RNA sequencing, respectively.
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