Targeting TSP-1 decreased periodontitis by attenuating extracellular matrix degradation and alveolar bone destruction

Int Immunopharmacol. 2021 Jul:96:107618. doi: 10.1016/j.intimp.2021.107618. Epub 2021 May 17.

Abstract

An important factor in periodontitis pathogenesis relates to a network of interactions of various cytokines. Thrombospondin-1 (TSP-1) is upregulated in several inflammatory diseases. We previously found that Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS)-induced TSP-1 production, and that TSP-1 simultaneously and effectively elevated inflammatory cytokines in THP-1 macrophages. This suggests that TSP-1 plays an important role in the pathology of periodontitis. However, the function of TSP-1 on oral cells is largely unknown. This study aimed to elucidate the underlying molecular mechanisms of TSP-1 in human periodontal fibroblasts (hPDLFs). We demonstrated that TSP-1 is highly expressed in the gingival crevicular fluid of patients with chronic periodontitis and in the inflammatory gingival tissues of rats. TSP-1 overexpression or treatment with recombinant human TSP-1(rTSP-1) promoted the expression of MMP-2, MMP-9 and RANKL/OPG in hPDLFs, while anti-TSP-1 inhibited cytokines production from P. gingivalis LPS-treated hPDLFs. Additional experiments showed that SB203580 (a special p38MAPK inhibitor) inhibited MMP-2, MMP-9 and RANKL/OPG expression induced by rTSP-1. Thus, TSP-1 effectively promoted P. gingivalis LPS-induced periodontal tissue (extracellular matrix (ECM) and alveolar bone) destruction by the p38MAPK signalling pathway, indicating that it may be a potential therapeutic target against periodontitis.

Keywords: Alveolar bone destruction; ECM degradation; Periodontitis; TSP-1; p38MAPK signalling pathway.

MeSH terms

  • Alveolar Bone Loss / drug therapy*
  • Alveolar Bone Loss / metabolism*
  • Alveolar Bone Loss / pathology
  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Extracellular Matrix / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gingiva / metabolism
  • Gingiva / pathology
  • Gingival Crevicular Fluid / chemistry
  • Gingival Crevicular Fluid / metabolism
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Osteoprotegerin / metabolism
  • Periodontitis / drug therapy*
  • Periodontitis / metabolism
  • Periodontitis / pathology
  • Primary Cell Culture
  • RANK Ligand / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Thrombospondin 1 / antagonists & inhibitors
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Up-Regulation

Substances

  • Cytokines
  • Osteoprotegerin
  • RANK Ligand
  • Recombinant Proteins
  • TNFRSF11B protein, human
  • TNFSF11 protein, human
  • Thrombospondin 1
  • thrombospondin 1, rat
  • thrombospondin-1, human
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9