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

• Published in: Scientific reports Vol. 12; no. 1; p. 18636
• Main Authors: Le, Hoa T., Golla, Kalyan, Karimi, Ryan, Hughes, Michael R., Lakschevitz, Flavia, Cines, Douglas B., Kowalska, M. Anna, Poncz, Mortimer, McNagny, Kelly M., Häkkinen, Lari, Kim, Hugh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-11-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80/86; 692/699/3020/3029; Angiogenesis Inhibitors - metabolism; Animals; Chemokines; Chondroitin ABC lyase; Chondroitin sulfate; Connective tissue diseases; Fibroblasts; Fibroblasts - metabolism; Gelatinase; Gelatinase A; Gingiva; Glycosaminoglycans; Heparan sulfate; Homeostasis; Humanities and Social Sciences; Humans; Inflammatory diseases; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 3 - metabolism; Metalloproteinase; Mice; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Periodontitis; Periodontitis - metabolism; Periodontium; Phosphorylation; Platelet factor 4; Platelet Factor 4 - metabolism; Platelets; Science; Science (multidisciplinary); Signal transduction; Sulfates; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-19850-w

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.