Spine degeneration in a murine model of chronic human tobacco smokers

D. Wang, L. A. Nasto, P. Roughley, A. S. Leme, A. M. Houghton, A. Usas, G. Sowa, J. Lee, L. Niedernhofer, S. Shapiro, J. Kang, N. Vo

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66 Scopus citations

Abstract

Objective: To investigate the mechanisms by which chronic tobacco smoking promotes intervertebral disc degeneration (IDD) and vertebral degeneration in mice. Methods: Three month old C57BL/6 mice were exposed to tobacco smoke by direct inhalation (4cigarettes/day, 5days/week for 6months) to model long-term smoking in humans. Total disc proteoglycan (PG) content [1,9-dimethylmethylene blue (DMMB) assay], aggrecan proteolysis (immunobloting analysis), and cellular senescence (p16INK4a immunohistochemistry) were analyzed. PG and collagen syntheses ( 35S-sulfate and 3H-proline incorporation, respectively) were measured using disc organotypic culture. Vertebral osteoporosity was measured by micro-computed tomography. Results: Disc PG content of smoke-exposed mice was 63% of unexposed control, while new PG and collagen syntheses were 59% and 41% of those of untreated mice, respectively. Exposure to tobacco smoke dramatically increased metalloproteinase-mediated proteolysis of disc aggrecan within its interglobular domain (IGD). Cellular senescence was elevated two-fold in discs of smoke-exposed mice. Smoke exposure increased vertebral endplate porosity, which closely correlates with IDD in humans. Conclusions: These findings further support tobacco smoke as a contributor to spinal degeneration. Furthermore, the data provide a novel mechanistic insight, indicating that smoking-induced IDD is a result of both reduced PG synthesis and increased degradation of a key disc extracellular matrix protein, aggrecan. Cleavage of aggrecan IGD is extremely detrimental as this results in the loss of the entire glycosaminoglycan-attachment region of aggrecan, which is vital for attracting water necessary to counteract compressive forces. Our results suggest identification and inhibition of specific metalloproteinases responsible for smoke-induced aggrecanolysis as a potential therapeutic strategy to treat IDD.

Original languageEnglish (US)
Pages (from-to)896-905
Number of pages10
JournalOsteoarthritis and Cartilage
Volume20
Issue number8
DOIs
StatePublished - Aug 2012

Bibliographical note

Funding Information:
This work was supported by the Albert B. Ferguson, Jr. M.D. Orthopaedic Fund of the Pittsburgh Foundation , 2010 ORS Collaborative Exchange Award to Nam Vo and Peter Roughley, and NIH grants AG033046 to Nam Vo, ES016114 to Laura Niedernhofer.

Keywords

  • Aggrecan
  • Intervertebral disc degeneration
  • Matrix metalloproteinases
  • Matrix proteoglycans
  • Tobacco smoking

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