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

doi:10.1016/j.jtauto.2019.100028

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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

10 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	100028
Tidsskrift	Journal of Translational Autoimmunity
Vol/bind	3
ISSN	2589-9090
DOI	https://doi.org/10.1016/j.jtauto.2019.100028
Status	Udgivet - 2020

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10.1016/j.jtauto.2019.100028Licens: CC BY-NC-ND

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Greisen, S. R., Kragstrup, T. W., Thomsen, J. S., Hansen, A. S., Krishnamurthy, A., Hørslev-Petersen, K., Hetland, M. L., Stengaard-Pedersen, K., Østergaard, M., Ørnbjerg, L. M., Junker, P., Sharpe, A. H., Freeman, G. J., Annamalai, L., Hvid, M., Moestrup, S. K., Hauge, E.-M., Catrina, A. I., & Deleuran, B. (2020). Programmed death ligand 2 - A link between inflammation and bone loss in rheumatoid arthritis. Journal of Translational Autoimmunity, 3, Artikel 100028. https://doi.org/10.1016/j.jtauto.2019.100028

@article{c9f5bfb7b9ed47fd9962e8c71277237e,

title = "Programmed death ligand 2 - A link between inflammation and bone loss in rheumatoid arthritis",

abstract = "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.",

keywords = "Autoimmunity, Co-inhibitory receptors, Osteoclasts, Ostoeimmunology, PD-L2, Rheumatoid arthritis",

author = "Greisen, {Stinne R} and Kragstrup, {Tue W} and Thomsen, {Jesper Skovhus} and Hansen, {Aida Solh{\o}j} and Akilan Krishnamurthy and Kim H{\o}rslev-Petersen and Hetland, {Merete Lund} and Kristian Stengaard-Pedersen and Mikkel {\O}stergaard and {\O}rnbjerg, {Lykke Midtb{\o}ll} and Peter Junker and Sharpe, {Arlene H} and Freeman, {Gordon J} and Lakshmanan Annamalai and Malene Hvid and Moestrup, {S{\o}ren K} and Ellen-Margrethe Hauge and Catrina, {Anca Irinel} and Bent Deleuran",

year = "2020",

doi = "10.1016/j.jtauto.2019.100028",

language = "English",

volume = "3",

journal = "Journal of Translational Autoimmunity",

issn = "2589-9090",

publisher = "Elsevier B.V.",

}

Greisen, SR , Kragstrup, TW , Thomsen, JS, Hansen, AS, Krishnamurthy, A, Hørslev-Petersen, K, Hetland, ML, Stengaard-Pedersen, K, Østergaard, M, Ørnbjerg, LM, Junker, P, Sharpe, AH, Freeman, GJ, Annamalai, L, Hvid, M , Moestrup, SK , Hauge, E-M, Catrina, AI & Deleuran, B 2020, 'Programmed death ligand 2 - A link between inflammation and bone loss in rheumatoid arthritis', Journal of Translational Autoimmunity, bind 3, 100028. https://doi.org/10.1016/j.jtauto.2019.100028

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

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.

KW - Autoimmunity

KW - Co-inhibitory receptors

KW - Osteoclasts

KW - Ostoeimmunology

KW - PD-L2

KW - Rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=85089756055&partnerID=8YFLogxK

U2 - 10.1016/j.jtauto.2019.100028

DO - 10.1016/j.jtauto.2019.100028

M3 - Journal article

C2 - 32743513

SN - 2589-9090

VL - 3

JO - Journal of Translational Autoimmunity

JF - Journal of Translational Autoimmunity

M1 - 100028

ER -

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

Abstract

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