Anti-inflammatory Effect of MAPK phosphatase-1 Local Gene Transfer in Inflammatory Bone Loss

Gene Ther. 2011 Apr;18(4):344-53. doi: 10.1038/gt.2010.139. Epub 2010 Nov 11.

Abstract

Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this study, rat macrophages transduced with recombinant adenovirus (Ad.)MKP-1 specifically dephosphorylated activated MAPKs induced by lipopolysaccharide (LPS) compared with control cells. Bone marrow macrophages from MKP-1 knockout (KO) mice exhibited higher interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and select chemokine compared with wild-type (WT) mice when stimulated by LPS. In addition, bone marrow cultures from MKP-1 KO mice exhibited significantly more osteoclastogenesis induced by LPS than when compared with WT mice. Importantly, MKP-1 gene transfer in bone marrow cells of MKP-1 KO mice significantly decreased IL-6, IL-10, TNF-α and chemokine levels, and formed fewer osteoclasts induced by LPS than compared with control group of cells. Furthermore, MKP-1 gene transfer in an experimental periodontal disease model attenuated bone resorption induced by LPS. Histological analysis confirmed that periodontal tissues transduced with Ad. MKP-1 exhibited less infiltrated inflammatory cells, less osteoclasts and less IL-6 than compared with rats of control groups. These studies indicate that MKP-1 is a key therapeutic target to control of inflammation-induced bone loss.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alveolar Bone Loss / genetics*
  • Animals
  • Dual Specificity Phosphatase 1 / genetics*
  • Gene Transfer Techniques
  • Immunity, Innate
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Osteoclasts
  • Phosphorylation
  • Rats

Substances

  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse