Gene transfer of the catabolic inhibitor TIMP-1 increases mesured proteoglycans in cells from degenerated human intervertebral discs

Corey J. Wallach, Satoshi Sobajima, Yasuhiko Watanabe, Joseph S. Kim, Helga I. Georgescu, Paul Robbins, Lars G. Gilbertson, James D. Kang

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

Study Design. Cells from degenerated intervertebral discs were transduced with an adenoviral vector delivering cDNA of the catabolic inhibitor, TIMP-1, and alterations in the measured proteoglycan were assessed. Objectives. To assess the potential of TIMP-1 to favorably modify the proteoglycan content of degenerated intervertebral disc cells. Summary of Background Data. Gene therapy with anabolic factors has resulted in increased proteoglycan synthesis in intervertebral disc cells. Biochemical analysis of degenerated discs has revealed elevated levels of the catabolic enzymes, matrix metalloproteinase, suggesting an intimate role of these factor in the degenerative process. The use of TIMP-1, an endogenous inhibitor of matrix metalloproteinase, via gene therapy may provide an additional method to after the degenerative processes occurring in the intervertebral disc. Materials and Methods. Degenerated intervertebral disc were isolated from eight patients undergoing elective surgical procedures. Cells were cultured in monolayer and transduced with different concentrations of either an adenoviral-tissue inhibitor of metalloproteinase-1 (Ad-TIMP-1) or adenoviral-bone morphogenic protein-2 (Ad-BMP-2) construct. Cells were cultured in a three-dimensional pellet and proteoglycan synthesis was assessed via 35S-sulfur incorporation. Results. Gene delivery of TIMP-1 and BMP-2 increased measured proteoglycan synthesis at each concentration assessed. IVD cells treated with Ad-TIMP-1 demonstrated an optimal response at a multiplicity of infection (MOI) of 100. Cells treated with Ad-BMP-2 demonstrated a progressive increase in proteoglycan synthesis with increasing viral concentrations. Conclusions. Successful delivery of the anticatabolic gene, TIMP-1, results in increased measured proteoglycan in cultured degenerated disc cells. This finding supports catabolic inhibition as a promising avenue of research for the treatment of degenerative disc disease via gene therapy.

Original languageEnglish (US)
Pages (from-to)2331-2337
Number of pages7
JournalSpine
Volume28
Issue number20
DOIs
StatePublished - Oct 15 2003
Externally publishedYes

Keywords

  • Bone morphogenic proetin-2
  • Disc degeneration
  • Gene therapy
  • Matrix metalloproteinases
  • Tissue inhibitor of matrix metalloproteinases-1

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