title: Impaired intervertebral disc development and premature disc degeneration in mice with notochord-specific deletion of CCN2.
abstract: OBJECTIVE
  Currently, our ability to treat intervertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue-specific localization of CCN proteins and to characterize their role in IVD tissues during embryonic development and age-related degeneration by using a mouse model of notochord-specific CCN2 deletion.
  
  
  METHODS
  Expression of CCN proteins was assessed in IVD tissues from wild-type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord-derived tissues, we generated notochord-specific CCN2-null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed.
  
  
  RESULTS
  Loss of the CCN2 gene in notochord-derived cells disrupted the formation of IVDs in embryonic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly increased levels of type I collagen within the nucleus pulposus. CCN2-knockout mice also had altered expression of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord-specific CCN2 deletion accelerated age-associated degeneration of IVDs.
  
  
  CONCLUSIONS
  Using a notochord-specific gene targeting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age-associated tissue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration.
authors.affiliation: Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jake
authors.initials: J
authors.lastname: Bedore
authors.forename: Wei
authors.initials: W
authors.lastname: Sha
authors.forename: Matthew R
authors.initials: MR
authors.lastname: McCann
authors.forename: Shangxi
authors.initials: S
authors.lastname: Liu
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.forename: Cheryle A
authors.initials: CA
authors.lastname: Séguin
mesh_terms: D053674:Aggrecans / Q000502:physiology; D000375:Aging / Q000502:physiology; D000818:Animals; D024042:Collagen Type I / Q000502:physiology; D024043:Collagen Type II / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D007403:Intervertebral Disc / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology*; D055959:Intervertebral Disc Degeneration / Q000473:pathology / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009672:Notochord / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D053674:Aggrecans; C526318:CCN2 protein, mouse; D024042:Collagen Type I; D024043:Collagen Type II; D055513:Connective Tissue Growth Factor