Developmental Pathways of Immature CD11c+ Myeloid Dendritic Cells (mDCs) for Bona Fide Osteoclastogenesis Revisited: A Narrative Review

Recent studies support that hematopoietic stem cell (HSC)-derived myeloid dendritic cells, monocytes/macrophages (Mo/Mϕ), and osteoclast precursors (OCps) share common progenitor(s) during development. This occurs mainly through receptor activator of NF-κB ligand (RANKL) signaling via its cytoplasmic adaptor protein complex (TRAF6) to subsequent osteoclastogenesis for bone loss and/or remodeling. Presently, mounting new evidence suggests that erythro-myeloid progenitor (EMP)-derived macrophages (Mϕ) and HSC-derived monocytes (Mo) produce embryonic, fetal, and postnatal OCp pools (i.e., primitive OCp), pinpointing a complex network of multiple OCp developmental origins. However, their ontogenic developments, lineage interactions, and contributions to the alternative osteoclastogenesis—in contrast to overall bone remodeling or loss—remain elusive. Interestingly, studies have also elucidated the contributions of immature CD11c+ myeloid DC-like OCps to osteoclastogenesis, with or without the classical so-called Mo/Mϕ-derived OCp subsets, and described that CD11c+ myeloid DCs (mDCs) develop into functionally active OCs; meanwhile, the cytokine TGF-β mediates a stepwise regulation of de novo immature mDCs/OCps through distinct crosstalk(s) with IL-17, an unrecognized interaction featuring TRAF6(−/−)CD11c+ mDDOCps that coexist and proficiently colocalize in the local environment to drive a bona fide route for alternative osteoclastogenesis in vivo. Collectively, new findings—critically hinged on progenitor osteoclastogenic pathways (primitive OCps, mDCs/OCps, osteomorphs, etc.) and involving classical and/or alternative routes to inflammation-induced bone loss—are discussed via the illustrated schemes. This review highlights plausible ontogenic vs. principal or alternative developmental paths and their consequential downstream effects.