Distinct cross talk of IL-17 & TGF-β with the immature CD11c⁺ TRAF6^(-/-) -null myeloid dendritic cell-derived osteoclast precursor (mDDOCp) may engage signaling toward an alternative pathway of osteoclastogenesis for arthritic bone loss in vivo

Background: Dendritic cells (DCs), though borne heterogeneous, are the most potent antigen-presenting cells, whose critical functions include triggering antigen-specific naïve T-cell responses and fine-tuning the innate versus adaptive immunity at the osteo-immune and/or mucosal mesenchyme interface. We previously reported that immature myeloid-CD11c⁺ DCs/mDCs may act like osteoclast (OC) precursors (OCp/mDDOCp) capable of developing into functional OCs via an alternative pathway of inflammation-induced osteoclastogenesis; however, what are their contribution and signaling interactions with key osteotropic cytokines (i.e., interleukin-17 [IL-17] and transforming growth factor-β [TGF-β]) to bearing such inflammatory bone loss in vivo remain unclear to date.

Methods: Herein, we employed mature adult bone marrow-reconstituted C57BL/6 TRAF6^(-/-) -null chimeras without the classical monocyte/macrophage (Mo/Mϕ)-derived OCs to address their potential contribution to OCp/mDDOCp-mediated osteoclastogenesis in the chicken type-II-collagen (CC-II)-induced joint inflammation versus arthritic bone loss and parallel associations with the double-positive CD11c⁺ TRAP⁺ TRAF6-null^(-/-) DC-like OCs detected in vivo via the quantitative dual-immunohistochemistry and digital histomorphometry for analyses.

Results: The resulting findings revealed the unrecognized novel insight that (i) immature myeloid-CD11c⁺ TRAF6^(-/-) TRAP⁺ DC-like OCs were involved, co-localized, and strongly associated with joint inflammation and bone loss, independent of the Mo/Mϕ-derived classical OCs, in CC-II-immunized TRAF6^(-/-) -null chimeras, and (ii) the osteotropic IL-17 may engage distinct crosstalk with CD11c⁺ mDCs/mDDOCp before developing the CD11c⁺ TRAP⁺ TRAF6^(-/-) OCs via a TGF-β-dependent interaction toward inflammation-induced arthritic bone loss in vivo.

Conclusion: These results confirm and substantiate the validity of TRAF6^(-/-) -null chimeras to address the significance of immature mCD11c⁺ TRAP⁺ DC-like OCs/mDDOCp subset for an alternative pathway of arthritic bone loss in vivo. Such CD11c⁺ mDCs/mDDOCp-associated osteoclastogenesis through the step-wise twist-in-turns osteo-immune cross talks are thereby theme highlighted to depict a summative re-visitation proposed.