TY - JOUR
T1 - Programmed death ligand 2 - A link between inflammation and bone loss in rheumatoid arthritis
AU - Greisen, Stinne R
AU - Kragstrup, Tue W
AU - Thomsen, Jesper Skovhus
AU - Hansen, Aida Solhøj
AU - Krishnamurthy, Akilan
AU - Hørslev-Petersen, Kim
AU - Hetland, Merete Lund
AU - Stengaard-Pedersen, Kristian
AU - Østergaard, Mikkel
AU - Ørnbjerg, Lykke Midtbøll
AU - Junker, Peter
AU - Sharpe, Arlene H
AU - Freeman, Gordon J
AU - Annamalai, Lakshmanan
AU - Hvid, Malene
AU - Moestrup, Søren K
AU - Hauge, Ellen-Margrethe
AU - Catrina, Anca Irinel
AU - Deleuran, Bent
N1 - COPECARE
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1016/j.jtauto.2019.100028
DO - 10.1016/j.jtauto.2019.100028
M3 - Journal article
C2 - 32743513
SN - 2589-9090
VL - 3
SP - 100028
EP - 100038
JO - Journal of Translational Autoimmunity
JF - Journal of Translational Autoimmunity
ER -