Platelet factor 4 (CXCL4/PF4) upregulates matrix metalloproteinase-2 (MMP-2) in gingival fibroblasts

Hoa T. Le, Kalyan Golla, Ryan Karimi, Michael R. Hughes, Flavia Lakschevitz, Douglas B. Cines, M. Anna Kowalska, Mortimer Poncz, Kelly M. McNagny, Lari Häkkinen, Hugh Kim

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Periodontitis is a chronic inflammatory disease characterized by the release of matrix metalloproteinases (MMPs) from resident connective tissue cells in tooth-supporting tissues (periodontium). Platelet activation, and the attendant release of pro-inflammatory chemokines such as platelet factor 4 (CXCL4/PF4), are associated with periodontitis although the associated biochemical pathways remain undefined. Here we report that recombinant PF4 is internalized by cultured human gingival fibroblasts (hGFs), resulting in significant (p < 0.05) upregulation in both the production and release of MMP-2 (gelatinase A). This finding was corroborated by elevated circulating levels of MMP-2 (p < 0.05) in PF4-overexpressing transgenic mice, relative to controls. We also determined that PF4 induces the phosphorylation of NF-κB; notably, the suppression of NF-κB signaling by the inhibitor BAY 11-7082 abrogated PF4-induced MMP-2 upregulation. Moreover, the inhibition of surface glycosaminoglycans (GAGs) blocked both PF4 binding and NF-κB phosphorylation. Partial blockade of PF4 binding to the cells was achieved by treatment with either chondroitinase ABC or heparinase III, suggesting that both chondroitin sulfate and heparan sulfate mediate PF4 signaling. These results identify a novel pathway in which PF4 upregulates MMP-2 release from fibroblasts in an NF-κB- and GAG-dependent manner, and further our comprehension of the role of platelet signaling in periodontal tissue homeostasis.

Original languageEnglish (US)
Article number18636
JournalScientific reports
Volume12
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
The authors thank Takehide Murakami (UBC Biomedical Research Centre) for assistance with mouse breeding and genotyping, as well as Angela Tether for editorial assistance. This study was supported by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-156341), a CIHR Clinician-Scientist Salary Award (MC2-127872), and a Michael Smith Foundation for Health Research (MSFHR) Scholar Award (to HK). Infrastructural support for this project was provided by a John Evans Leaders Fund grant from the Canada Foundation for Innovation (CFI).

Funding Information:
The authors thank Takehide Murakami (UBC Biomedical Research Centre) for assistance with mouse breeding and genotyping, as well as Angela Tether for editorial assistance. This study was supported by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-156341), a CIHR Clinician-Scientist Salary Award (MC2-127872), and a Michael Smith Foundation for Health Research (MSFHR) Scholar Award (to HK). Infrastructural support for this project was provided by a John Evans Leaders Fund grant from the Canada Foundation for Innovation (CFI).

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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