Abstract
ObjectiveThe 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.MethodsBone mineral density and bone microstructure were examined in PD-1 and PD-L1 knockout (KO) mice and compared with wild-type (WT) mice. Receptor activator of nuclear factor kappa-B 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. sPD-1 was measured in chronic and early (e)RA patients and correlated to markers of disease activity and radiographic scores.ResultsPD-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 with disease activity markers in eRA patients. Sustained elevated sPD-1 levels indicated ongoing inflammation and were associated with increased radiographic progression.ConclusionThe 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.
Highlights
The programmed death-1 (PD-1) pathway is essential for maintaining self-tolerance, and if impaired, autoimmune diseases can develop [1, 2]
The bone density was significantly reduced and the bone microstructure was significantly deteriorated at 8 weeks of age in both PD-1 KO and PD-L1 KO mice (Figure 1A)
The diaphyseal cortical bone was mainly affected in PD-L1 KO mice, with a decreased bone area (B.Ar; PD-L1 KO: 0.79 ± 0.07 mm2, WT: 0.93 ± 0.08 mm2, p < 0.05), as well as a decreased cortical thickness (Ct.Th) and an increased marrow area (Ma.Ar) (Figures 1B, D and Supplementary Figure S1)
Summary
The programmed death-1 (PD-1) pathway is essential for maintaining self-tolerance, and if impaired, autoimmune diseases can develop [1, 2]. The PD-1 pathway comprises the PD-1 receptor, which is mainly expressed by activated T and B cells, and by T regulatory cells and exhausted T cells (Tex). Activation of the PD-1 pathway decreases inflammation. The system is complex and regulates the activation of T helper cells and of regulatory T cells and follicular T helper cells, as well as antibody production [5]. Since PD-1 expression is increased upon T-cell stimulation, many autoimmune diseases are characterized by upregulation of PD-1 [7, 8]. Studies in mice confirm that impairment of the PD-1 pathway results in increased severity of autoimmune diseases [9–12]
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