Distinct pathways of osteoclastogenesis in inflammatory arthritis
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Abstract
Inflammatory arthritis results from infiltration of inflammatory cells into the synovial tissue surrounding diarthrodial joints. These cell infiltrates produce cytokines and other factors causing inflammation and the formation of bone resorbing osteoclasts which cause destruction of cartilage and bone1. Osteoclasts are large multinucleated cells that are key in the development and maintenance of the skeleton4. They allow for the modelling of bone and tooth eruption in early life, and the maintenance and remodeling of bone during adulthood in healthy individuals12. Two distinct osteoclast lineages have been reported. During embryogenesis, osteoclasts that colonize developing ossification centers of long bones derived from erythromyeloid progenitors (EMPs); after birth hematopoietic stem cell (HSCs)-derived progenitors fuse with pre-existing EMP-derived osteoclasts and gradually replace them, however each lineage contribution is critical to maintain osteoclast function throughout life12. Jacome-Galarza C.E., et al., 2019, generated mice that lack either EMP-derived osteoclasts (Tnfrsf11aCre;Csf1rfl/fl, lethal after birth), or mice that lacked HSC-derived osteoclast (Flt3Cre;Tnfrsf11afl/fl) which are born normally but develop osteopetrosis with age12.Osteoclasts are normally found in long bones associated to trabecular bone but are absent in healthy synovial tissues, however, under inflammatory conditions, osteoclasts are found on bone periosteal surfaces that are in contact with the inflamed synovium, leading to bone erosions along all surface of bone. The diagnosis of bone erosions in inflammatory arthritis is essential to the prognosis of the disease3. Osteoclasts develop from the cell fusion of osteoclast precursors, which depend on M-CSF and RANKL for cell survival and differentiation6. The resorption capacity of osteoclasts has been suggested to activate independent of RANK signaling in inflammatory conditions and shown to depend on inflammatory cytokines expressed in inflamed synovium including TNF, IL-6, and IL-19. Some reports indicate that macrophages can differentiate into osteoclasts under these conditions24, however, the lineage of origin is unknown. We hypothesize that osteoclasts derived from both HSC- and EMP-derived precursors differentiate in inflamed synovium. To test this hypothesis, a conditional KO mouse which genetically deletes Tnfrsf11a (which codes for RANK) in all HSC-derived cells expressing Flt3 and can also expressed YFP for cell lineage tracing was developed (Flt3Cre; Tnfrsf11afl/fl;Rosa26LSL-YFP). In these mice, under arthritic conditions, HSC-derived osteoclasts were reduced in the inflamed synovium of hind paws. Interestingly, the majority of osteoclasts identified in the inflamed synovium in the absence of RANK (deleted in HSC-derived cells) were potentially consequent from EMP-derived cells and were capable of causing bone erosion.
In addition, inflammatory Ly6C+ monocytes, which are precursors of osteoclasts in the bone marrow, were quantified in the inflamed synovium of hind paws in Flt3Cre; Tnfrsf11afl/fl;Rosa26LSL-YFP KO mice and found to be reduced in inflamed synovium when compared to WT littermates, suggesting that deletion of RANK in these cells prevents their differentiation to osteoclasts in inflamed synovium. Although inconclusive, these preliminary results suggest that in inflammatory arthritis, osteoclasts might originate from at least two different cell sources that are also different in origin and regulated by distinct signaling pathways.
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2023