Local aggressive growth of odontogenic keratocysts (OKCs) can cause serious bone destruction,
even resulting in pathologic fractures of the mandible. With the aim to explore the
mechanism of osteoclastogenesis in OKCs, the role of programmed cell death ligand
1 (PD-L1), a key immune checkpoint, in OKCs and its relationship with the M2 isoform
of pyruvate kinase (PKM2), a key enzyme of glycolysis, were investigated. The data
from immunohistochemistry, real-time quantitative PCR, Western blot analysis, and
flow cytometry showed that the expression level of PD-L1 was significantly increased
in the stroma and fibroblasts of OKCs (OKC-Fs) when compared with oral mucosa. Double-labeling
staining demonstrated that osteoclasts in OKCs spatially interacted with PD-L1–positive
OKC-Fs. Exogenous expression of PD-L1 in OKC-Fs promoted osteoclastogenesis when OKC-Fs
were co-cultured with osteoclast precursors (RAW264.7 cells). Because OKC-Fs exhibit
energy dependency and acquire energy from PKM2-mediated glycolysis, this study generated
stable PKM2 knockdown OKC-Fs using shRNAs against PKM2, and found that PD-L1 expression
level was decreased by PKM2 knockdown. Furthermore, Spearman rank correlation analysis
showed that there was a positive correlation between the immunostaining of PKM2 and
PD-L1 in OKC samples. In addition, double-labeling immunofluorescence showed colocalizations
between PKM2 and PD-L1 in the fibrous tissue walls of OKCs. In conclusion, PD-L1 in
fibroblasts promotes osteoclastogenesis in OKCs, which is regulated by PKM2.
Graphical abstract
Graphical Abstract
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Article info
Publication history
Published online: December 09, 2022
Accepted:
November 22,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by the National Natural Science Foundation of China grants 81800994 (W.Z.), 81741082 (Y.C.), and 81972548 (C.H.); and Wuhan Science and Technology Bureau grant 2020020601012212 (Y.C.).
T.Z. and R.W. contributed equally to this work.
Disclosures: None declared.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
