Comparison of inbred mouse strains shows diverse phenotypic outcomes of intervertebral disc aging

Abstract

Intervertebral disc degeneration presents a wide spectrum of clinically degenerative disc phenotypes; however, the contribution of genetic background to the degenerative outcomes has not been established. We characterized the spinal phenotype of 3 mouse strains with varying cartilage‐regenerative potential at 6 and 23 months: C57BL/6, LG/J and SM/J. All strains showed different aging phenotypes. Importantly, LG/J mice showed an increased prevalence of dystrophic disc calcification in caudal discs with aging. Quantitative‐histological analyses of LG/J and SM/J caudal discs evidenced accelerated degeneration compared to BL6, with cellular disorganization and cell loss together with fibrosis of the NP, respectively. Along with the higher grades of disc degeneration, SM/J, at 6M, also differed the most in terms of NP gene expression compared to other strains. Moreover, although we found common DEGs between BL6 and LG/J aging, most of them were divergent between the strains. Noteworthy, the common DEGs altered in both LG/J and BL6 aging were associated with inflammatory processes, response to stress, cell differentiation, cell metabolism and cell division. Results suggested that disc calcification in LG/J resulted from a dystrophic calcification process likely aggravated by cell death, matrix remodelling, changes in calcium/phosphate homeostasis and cell transformation. Lastly, we report 7 distinct phenotypes of human disc degeneration based on transcriptomic profiles, that presented similar pathways and DEGs found in aging mouse strains. Together, our results suggest that disc aging and degeneration depends on the genetic background and involves changes in various molecular pathways, which might help to explain the diverse phenotypes seen during disc disease.

Genetic murine models of spinal development and degeneration provide valuable insights into intervertebral disc pathobiology

“…ADAMTS-4 knockout mice, surprisingly, do not show any defects in skeletal development, growth, or remodelling, and no alterations in the growth of their long bones (Glasson et al, 2004). Likewise ADAMTS-5 knockout mice have no skeletal developmental abnormalities, although deletion of ADAMTS-5 effectively prevents cartilage destruction in a murine osteoarthritis model and is shown to protect from chronic tobacco smoke-induced disc degeneration (Ngo et al, 2017). These findings are consistent with the view that ADAMTS-5 is largely responsible for the turnover of murine aggrecan PRG4 knockout Increased torsional modulus and reduced transverse major diameter and height.…”

“…Furthermore, domain IV of mouse perlecan contains less IgG repeats than human perlecan. Consequently, its core protein is ~ 40 kDa smaller than the human counterpart (Kallunki and Tryggvason, 1992;Noonan et al, 1991). Mouse perlecan also contains an RGD cell attachment sequence in domain III, which is absent in human perlecan (Chakravarti et al, 1995), although a cell adhesion site in domain IV has been identified in human perlecan (Farach-Carson et al, 2008) indicating that the overall functionality of the molecule is preserved between the species.…”

“…It is worth noting here that mice deficient in the transcription factor BACH-1 are less impacted by annular puncture. BACH-1 deficiency results in increased levels of HO-1, which protects disc cells from oxidative stress (Ohta et al, 2012).…”

“…Glasson et al, 2004 ADAMTS-5 knockout Protective against cartilage destruction and chronic tobacco smoke induced disc degeneration. Ngo et al, 2017 MT1-MMP knockout Inadequate collagen turnover, dwarfism, kyphosis, accelerated age-related osteoarthritic changes evident in axial skeleton. Holmbeck et al, 1999 SPARC knockout Endplate calcification and sclerosis.…”

“…This complex formation is important for the correct presentation of the FGFs to FGFRs, their subsequent oligomerisation, activation to initiate cell signalling through the cytoplasmic tail of the FGFRs, and subsequent downstream effects on cell proliferation and differentiation (Chang et al, 2000;Chuang et al, 2010;Knox et al, 2001;Knox and Whitelock, 2006). Perlecan contains multiple modules that are homologous to the LDL receptor (Murdoch et al, 1992;Noonan et al, 1991). When expressed on cells, domain II of perlecan binds and internalises LDL in a similar manner to LRP6 (Fuki et al, 2000).…”