Greisen Stinne R, Kragstrup Tue W, Thomsen Jesper Skovhus, Hansen Aida Solhøj, Krishnamurthy Akilan, Hørslev-Petersen Kim, Hetland Merete Lund, Stengaard-Pedersen Kristian, Østergaard Mikkel, Ørnbjerg Lykke Midtbøll, Junker Peter, Sharpe Arlene H, Freeman Gordon J, Annamalai Lakshmanan, Hvid Malene, Moestrup Søren K, Hauge Ellen-Margrethe, Catrina Anca Irinel, Deleuran Bent
Dept. of Biomedicine, Aarhus University, Denmark.
Dept. of Rheumatology, Aarhus University Hospital, Denmark.
J Transl Autoimmun. 2019 Dec 18;3:100028. doi: 10.1016/j.jtauto.2019.100028. eCollection 2020.
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.
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.
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.
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.
活动期类风湿关节炎（RA）伴有四肢和中轴骨量流失增加，这与炎症程度密切相关。程序性死亡-1（PD-1）通路对于维持外周免疫耐受很重要，其配体PD-L2最近已被证明与骨形态发生蛋白活性有关。在此，我们报告PD-L2在RA骨免疫学中起核心作用。
通过显微CT评估野生型（WT）和PD-L2基因敲除小鼠的股骨骨密度（BMD）和小梁骨微结构。破骨细胞由RA滑膜液单核细胞和外周血单核细胞生成。通过抗酒石酸酸性磷酸酶（TRAP）活性以及在存在抗瓜氨酸化蛋白抗体（ACPA）的情况下骨侵蚀的发展来评估重组PD-L2的作用。测量单独使用甲氨蝶呤或与TNF抑制剂阿达木单抗联合治疗的早期（e）RA患者（n = 103）的血浆可溶性（s）PD-L2水平。
PD-L2基因敲除小鼠的BMD降低，小梁骨微结构恶化，这与RANKL/OPG通路无关。PD-L2降低破骨细胞中的TRAP活性，并减少ACPA诱导的侵蚀。在RA滑膜中，PD-L2高度表达，尤其是在内衬层，eRA患者的血浆sPD-L2水平升高，并随治疗而降低。在开始使用甲氨蝶呤和安慰剂治疗两年后，一年内的sPD-L2水平与侵蚀进展呈负相关。
PD-L2调节RA中的骨稳态。我们的研究结果为免疫系统与骨稳态之间的关系提供了新的见解，并提示了一个限制RA炎症性骨丢失的潜在治疗靶点。
