Programmed death ligand 2 – A link between inflammation and bone loss in rheumatoid arthritis

Stinne R. Greisen*, Tue W. Kragstrup, Jesper Skovhus Thomsen, Aida Solhøj Hansen, Akilan Krishnamurthy, Kim Hørslev-Petersen, Merete Lund Hetland, Kristian Stengaard-Pedersen, Mikkel Østergaard, Lykke Midtbøll Ørnbjerg, Peter Junker, Arlene H. Sharpe, Gordon J. Freeman, Lakshmanan Annamalai, Malene Hvid, Søren K. Moestrup, Ellen Margrethe Hauge, Anca Irinel Catrina, Bent Deleuran

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Objective: Active rheumatoid arthritis (RA) is accompanied by increased appendicular and axial bone loss, closely associated to the degree of inflammation. The programmed death-1 (PD-1) pathway is important for maintaining peripheral tolerance, and its ligand PD-L2 has recently been associated with bone morphogenetic protein activity. Here, we report that PD-L2 plays a central role in RA osteoimmunology. Methods: Femoral bone mineral density (BMD) and trabecular bone microstructure were evaluated by micro-CT in wild type (WT) and PD-L2−/− mice. Osteoclasts were generated from RA synovial fluid mononuclear cells and peripheral blood monocytes. The effects of recombinant PD-L2, was evaluated by tartrate-resistant acid phosphatase (TRAP) activity and the development of bone erosions in the presence of anti-citrullinated protein antibodies (ACPA). Plasma soluble (s)PD-L2 levels were measured in patients with early (e)RA (n ​= ​103) treated with methotrexate alone or in combination with the TNF inhibitor Adalimumab. Results: PD-L2−/− mice had a decreased BMD and deteriorated trabecular bone microstructure that was not related to the RANKL/OPG pathway. PD-L2 decreased TRAP activity in osteoclasts and decreased ACPA-induced erosions. In the RA synovial membrane PD-L2 was highly expressed especially in the lining layer and plasma sPD-L2 levels were increased in eRA patients and decreased with treatment. One-year sPD-L2 correlated inversely with erosive progression two years after treatment initiation with methotrexate and placebo. Conclusion: PD-L2 regulates bone homeostasis in RA. Our findings provide new insight into the relationship between the immune system and bone homeostasis, and suggest a potential therapeutic target for limiting inflammatory bone loss in RA.

Original languageEnglish
Article number100028
JournalJournal of Translational Autoimmunity
Number of pages10
Publication statusPublished - 2020


  • Autoimmunity
  • Co-inhibitory receptors
  • Osteoclasts
  • Ostoeimmunology
  • PD-L2
  • Rheumatoid arthritis


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