A novel mouse model of intervertebral disc degeneration shows altered cell fate and matrix homeostasis

Matrix Biol. 2018 Sep;70:102-122. doi: 10.1016/j.matbio.2018.03.019. Epub 2018 Mar 29.

Abstract

Intervertebral disc degeneration and associated low back and neck pain is a ubiquitous health condition that affects millions of people world-wide, and causes high incidence of disability and enormous medical/societal costs. However, lack of appropriate small animal models with spontaneous disease onset has impeded our ability to understand the pathogenetic mechanisms that characterize and drive the degenerative process. We report, for the first time, early onset spontaneous disc degeneration in SM/J mice known for their poor regenerative capacities compared to "super-healer" LG/J mice. In SM/J mice, degenerative process was marked by decreased nucleus pulposus (NP) cellularity and changes in matrix composition at P7, 4, and 8 weeks with increased severity by 17 weeks. Distinctions between NP and annulus fibrosus (AF) or endplate cartilage were lost, and NP and AF of SM/J mice showed higher histological grades. There was increased NP cell death in SM/J mice with decreased phenotypic marker expression. Polarized microscopy and FTIR spectroscopy demonstrated replacement of glycosaminoglycan-rich NP matrix with collagenous fibrous tissue. The levels of ARGxx were increased in, indicating higher aggrecan turnover. Furthermore, an aberrant expression of collagen X and MMP13 was observed in the NP of SM/J mice, along with elevated expression of Col10a1, Ctgf, and Runx2, markers of chondrocyte hypertrophy. Likewise, expression of Enpp1 as well as Alpl was higher, suggesting NP cells of SM/J mice promote dystrophic mineralization. There was also a decrease in several pathways necessary for NP cell survival and function including Wnt and VEGF signaling. Importantly, SM/J discs were stiffer, had decreased height, and poor vertebral bone quality, suggesting compromised motion segment mechanical functionality. Taken together, our results clearly demonstrate that SM/J mouse strain recapitulates many salient features of human disc degeneration, and serves as a novel small animal model.

Keywords: Animal models; Hypertrophy; Intervertebral disc degeneration; LG/J; Matrix degradation; Nucleus pulposus; SM/J.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans / genetics
  • Aggrecans / metabolism
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism
  • Animals
  • Annulus Fibrosus / metabolism*
  • Annulus Fibrosus / pathology
  • Cell Death
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Collagen Type X / genetics
  • Collagen Type X / metabolism
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Disease Models, Animal*
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix / pathology
  • Female
  • Gene Expression Regulation*
  • Glycosaminoglycans / metabolism
  • Homeostasis / genetics
  • Humans
  • Intervertebral Disc Degeneration / genetics*
  • Intervertebral Disc Degeneration / metabolism
  • Intervertebral Disc Degeneration / pathology
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Mice, Transgenic
  • Nucleus Pulposus / metabolism*
  • Nucleus Pulposus / pathology
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Aggrecans
  • CCN2 protein, mouse
  • Col10a1 protein, mouse
  • Collagen Type X
  • Core Binding Factor Alpha 1 Subunit
  • Glycosaminoglycans
  • Runx2 protein, mouse
  • Vascular Endothelial Growth Factor A
  • Wnt Proteins
  • vascular endothelial growth factor A, mouse
  • Connective Tissue Growth Factor
  • ALPL protein, mouse
  • Alkaline Phosphatase
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Pyrophosphatases