AUTHOR=Greisen Stinne R. , Kragstrup Tue W. , Thomsen Jesper Skovhus , Hørslev-Pedersen Kim , Hetland Merete Lund , Stengaard-Pedersen Kristian , Østergaard Mikkel , Ørnbjerg Lykke , Junker Peter , Sharpe Arlene H. , Freeman Gordon J. , Hvid Malene , Moestrup Søren K. , Hauge Ellen Margrethe , Deleuran Bent 

TITLE=The Programmed Death-1 Pathway Counter-Regulates Inflammation-Induced Osteoclast Activity in Clinical and Experimental Settings

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.773946

DOI=10.3389/fimmu.2022.773946

ISSN=1664-3224

ABSTRACT=Objective: The programmed death-1 (PD-1) pathway is essential for maintaining self-tolerance, and plays an important role in autoimmunity, including rheumatoid arthritis (RA). Here, we investigated how membrane bound and soluble (s)PD-1 influence bone homeostasis during chronic inflammation, exemplified in RA. 
Methods: Bone mineral density and bone microstructure was examined in PD-1 and PD-L1 knock out (KO) mice and compared to wild type (WT) mice. Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL) was measured in serum, and the expression examined on activated bone marrow cells. Osteoclast formation was examined in cells from murine spleen and bone marrow, and from human synovial fluid cells. Soluble PD-1 (sPD-1) was measured in chronic and early (e)RA patients, and correlated to markers of disease activity and radiographic scores. 
Results:  PD-1 and PD-L1 KO mice showed signs of osteoporosis. This was supported by a significantly reduced trabecular bone volume fraction and deteriorated microstructure, as well as increased osteoclast formation and an increased RANKL/OPG ratio. The recombinant form of sPD-1 decreased osteoclast formation in vitro, but was closely associated to disease activity markers in eRA patients. Sustained elevated sPD-1 levels indicated ongoing inflammation and were associated with increased radiographic progression. 
Conclusion: The PD-1 pathway is closely associated with bone homeostasis, and lacking members of this pathway causes a deteriorated bone structure. The immunological balance in the microenvironment determines how the PD-1 pathway regulates osteoclast formation. In eRA patients, sPD-1 may serve as a biomarker, reflecting residual but clinically silent disease activity and radiographic progression.