PUBLICATION

3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease

Authors
Kague, E., Turci, F., Newman, E., Yang, Y., Brown, K.R., Aglan, M.S., Otaify, G.A., Temtamy, S.A., Ruiz-Perez, V.L., Cross, S., Royall, C.P., Witten, P.E., Hammond, C.L.
ID
ZDB-PUB-210902-3
Date
2021
Source
Bone research   9: 39 (Journal)
Registered Authors
Hammond, Chrissy, Kague, Erika, Witten, P. Eckhard
Keywords
none
MeSH Terms
none
PubMed
34465741 Full text @ Bone Res
Abstract
Back pain is a common condition with a high social impact and represents a global health burden. Intervertebral disc disease (IVDD) is one of the major causes of back pain; no therapeutics are currently available to reverse this disease. The impact of bone mineral density (BMD) on IVDD has been controversial, with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD. Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing. By taking a holistic 3D approach, we established an aging zebrafish model for spontaneous IVDD. Increased BMD in aging, detected by automated computational analysis, is caused by bone deformities at the endplates. However, aged zebrafish spines showed changes in bone morphology, microstructure, mineral heterogeneity, and increased fragility that resembled osteoporosis. Elements of the discs recapitulated IVDD symptoms found in humans: the intervertebral ligament (equivalent to the annulus fibrosus) showed disorganized collagen fibers and herniation, while the disc center (nucleus pulposus equivalent) showed dehydration and cellular abnormalities. We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K, leading to low and high BMD, respectively. Remarkably, we detected IVDD in both groups, demonstrating that low BMD does not protect against IVDD, and we found a strong correlation between high BMD and IVDD. Deep learning was applied to high-resolution synchrotron µCT image data to analyze osteocyte 3D lacunar distribution and morphology, revealing a role of sp7 in controlling the osteocyte lacunar 3D profile. Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu2790
    Point Mutation
    zf132TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      degenerative disc diseaseTAS
      1 - 1 of 1
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      Sequence Targeting Reagents
      Target Reagent Reagent Type
      ctskCRISPR1-ctskCRISPR
      ctskCRISPR2-ctskCRISPR
      1 - 2 of 2
      Show
      Fish
      Antibodies
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      GFPEFGGFP
      1 - 1 of 1
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      Mapping
      No data available