Immune modulation as a potential treatment strategy to salvage the bone metabolism after periprosthetic joint infection
Authors: Kienzle Arne , Ren Yi , Biederman Lara , Bandick Evgeniya , Jahn Denise , Du Weijie , Donner Stefanie , Tsitsilonis Serafeim , Duda Georg , Perka Carsten 
Published: May 2023

Background: In arthroplasty, periprosthetic joint infection (PJI) is one of the most disastrous postoperative complications with high long-term failure rates despite successful revision surgery. PJI causes a pro-inflammatory environment in the surrounding bone stock that subsequently results in compromised bone metabolism. This increases the risk for unstructured bone-resorption potentially leading to aseptic loosening. We hypothesize that PD-1-positive monocytes and monocyte-derived osteoclasts play a significant role in this pathology. In this study, we assessed the presence of PD-1-positive monocytes and their osteoclastogenic differentiation potential, as well as resulting osteoclast activity in PJI. We also investigated anti-PD-1-antibody as a potential salvage therapy. Material and Methods: Peripheral blood specimens were collected from 15 patients undergoing knee arthroplasty (ctrl) or prosthesis explantation due to PJI. Peripheral blood mononuclear cells were isolated and stained for CD33, CD11b, and CD14. Osteoclastic differentiation was induced ± PD-L1 and ± anti-PD-1-antibody. Osteoclast number and function were determined by pit assay, TRAP staining and qPCR. Results: Monocyte cell count (0.86±0.35 v 0.21±0.03/nl, p=.02) and PD-1 expression on monocytes (92.50±6.83 v 35.34±15.43%, p<.01) waselevated in patients with PJI. After differentiation, in PJI, total osteoclast surface area was larger (47.40±3.19% v 26.75±3.49%, p<.01) and increased significantly further (+64.04±1.72%, p<.01) after PD-L1 stimulation. Addition of PD-1 inhibitor reduced osteoclast surface area in PJI (36.51±3.95 v 64.04±1.72%, p<.01). Expression of osteoclast differentiation marker Nfatc1 and Ctsk were higher in the PJI group ( Nfatc1: 1.09±0.20 v 0.45±0.06, p<.01; Ctsk: 2.27±1.00 v 0.73±0.23, p=.02), but did not differ in Mmp9 and Acp5 expression. In PJI, the expression of all four genes were upregulated after PD-L1 stimulation, while PD-1 inhibitor treatment reversed this effect. PD-L1 stimulation led to increased osteoclast bone resorption compared to without stimulation (7.65±3.15 v 2.49±0.67%, p=.05), while addition of PD-1 inhibitor showed no influence in the ctrl group. In PJI, osteoclast surface resorption was increased after PD-L1 stimulation (20.69±6.54 v 8.06±1.54, p=.01). Conversely, osteoclast function was reduced after treatment with PD-1 inhibitor (4.23±0.55 v 8.06±1.54, p=.03). Conclusion: Elevated numbers of monocytic osteoclast-progenitor cells and increased osteoclastic differentiation and function may contribute to decreased bone volume and impact prosthesis osseointegration in patients with PJI. Our results show PD-L1 can stimulate osteoclast generation and function and that this can be reversed by PD-1 inhibitor. This effect is particularly prominent in PJI. Targeting PD-1 can be a potential therapy to inhibit monocyte-mediated osteoclastogenesis while retaining anti-microbial activity of macrophages to limit the impact of PJI on the bone stock. Dr. Arne Kienzle is participant in the BIH-Charité Junior Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. The authors wish to acknowledge the support of the non-profit German Arthritis Society (Deutsche Arthrose-Hilfe e.V.) and its president Helmut H. Huberti, MD by grant P482. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.