Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease

Osteoarthritis Cartilage. 2015 Apr;23(4):607-15. doi: 10.1016/j.joca.2014.12.012. Epub 2014 Dec 22.

Abstract

Objective: The matricellular protein NOV/CCN3, is implicated in osteoarthritis (OA) and targeted mutation of NOV in mice (Nov(del3)) leads to joint abnormalities. This investigation tested whether NOV is required for joint homeostasis and if its disruption causes joint degeneration.

Method: NOV expression in the adult mouse joint was characterized by immunohistochemistry. A detailed comparison of the joints of Nov(del3)-/- and Nov(del3)+/+ (wild-type) males and females at 2, 6 and 12 months of age was determined by X-ray, histology and immunohistochemistry.

Results: NOV protein was found in specific cells in articular cartilage, meniscus, synovium and ligament attachment sites in adult knees. Nov(del3)-/- males exhibited severe OA-like pathology at 12 months (OARSI score 5.0 ± 0.5, P < 0.001), affecting all tissues of the joint: erosion of the articular cartilage, meniscal enlargement, osteophytic outgrowths, ligament degeneration and expansion of fibrocartilage. Subchondral sclerosis and changes in extracellular matrix composition consistent with OA, were also seen. The density of articular cartilage cells in Nov(del3)+/+ knee joints is maintained at a constant level from 2 to 12 months of age whereas this is not the case in Nov(del3)-/- mice. Compared with age and sex-matched Nov(del3)+/+ mice, a significant increase in articular cartilage density was seen in Nov(del3)-/- males at 2 months, whereas a significant decrease was seen at 6 and 12 months in both Nov(del3)-/- males and females.

Conclusion: NOV is required for the maintenance of articular cartilage and for joint homeostasis, with disruption of NOV in ageing Nov(del3)-/- male mice causing OA-like disease.

Keywords: Joint homeostasis; NOV/CCN3; Osteoarthritis; Targeted mouse mutant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / physiology
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cartilage, Articular / pathology
  • Cartilage, Articular / physiopathology
  • Cell Count
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Disease Models, Animal
  • Female
  • Homeostasis / genetics
  • Homeostasis / physiology*
  • Knee Joint / diagnostic imaging
  • Knee Joint / pathology
  • Knee Joint / physiopathology*
  • Male
  • Mice
  • Mice, Knockout
  • Mutation / genetics*
  • Nephroblastoma Overexpressed Protein / deficiency
  • Nephroblastoma Overexpressed Protein / genetics*
  • Nephroblastoma Overexpressed Protein / physiology*
  • Osteoarthritis / genetics
  • Osteoarthritis / physiopathology*
  • Radiography
  • Risk Factors

Substances

  • Ccn3 protein, mouse
  • Nephroblastoma Overexpressed Protein