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Abstract
Objectives Osteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined.
Methods CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR, CD11c-Cre/CX3CR1-STOP-DTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OC of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs.
Results Targeting CD11c+ cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. OCs do not seem to be derived from CD11c+ cells expressing CX3CR1+, but from Zbtb46+conventional dendritic cells (cDCs) as all OCs in Zbtb46-Tomato fate reporter mice are Tomato+. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs.
Conclusion Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, which might open new avenues for therapeutic interventions in OC-mediated diseases.
- Arthritis, Experimental
- Autoimmunity
- Cytokines
- Osteoporosis
- Synovitis
Data availability statement
Data are available upon reasonable request. Data are available on reasonable request.
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Data availability statement
Data are available upon reasonable request. Data are available on reasonable request.
Footnotes
Handling editor Thomas Pap
Contributors AP, ES and SB conceived and designed the study. AP, ES, VS, MH, JB, BN, MK, RP and GD performed the experiments. BN performed histological processing of tissue samples. MKu, GS, GüS, SH, JSS, GK, KR, DA, PG provided input or key resources. AP, ES, MH, GH and SB analysed the data. AP, MK and SB wrote the manuscript. All authors read, revised and approved the final manuscript. SB is the guarantor of this study.
Funding We thank George Kollias for providing the hTNFTg/+ mice. This research was funded by the Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis and the Medical Scientific Fund of the Mayor of the City of Vienna (#20071). MH and JB were rewarded a DOC fellowship by the Austrian Academy of Sciences.
Competing interests DA reports about grants from Abbvie, Amgen, Galapagos, Lilly, and Sanofi; consulting fees and speakers’ bureau from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, and Sandoz. ES reports about speakers’ bureau from Lilly; support for meeting attendances from Pfizer, Bristol-Myers Squibb, Boehringer-Ingelheim and Astra Zeneca. GS reports about speakers’ bureau from Thermo Fisher Scientific. JSS reports about grants from AbbVie, Astra-Zeneca, Lilly and Galapagos; Royalties or licenses from Elsevier; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; participation on a data safety monitoring/advisory board for AstraZeneca. DA and JSS are editorial board members at the Annals of the Rheumatic Diseases. The remaining authors declare no competing interests.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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