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. 2018 Mar 1;13(3):e0193485.
doi: 10.1371/journal.pone.0193485. eCollection 2018.

A spontaneous model of spondyloarthropathies that develops bone loss and pathological bone formation: A process regulated by IL27RA-/- and mutant-p53

Denada Dibra  1 , Xueqing Xia  2 , Mihai Gagea  3 , Guillermina Lozano  1 , Shulin Li  2
Affiliations

A spontaneous model of spondyloarthropathies that develops bone loss and pathological bone formation: A process regulated by IL27RA-/- and mutant-p53

Denada Dibra et al. PLoS One. .

Abstract

Spondyloarthropathies, the second most frequently occurring form of chronic inflammatory arthritis, affects young adults in particular. However, a proper model with which to study the biology of this disease and to develop therapeutics is lacking. One of the most accepted animal models for this disease uses HLA-B27/Hu-β2m transgenic rats; however, only 30%-50% of male HLA-B27/Hu-β2m rats develop spontaneous, clinically apparent spondylitis and have a variable time until disease onset. Here, we report a high-incidence, low-variation spontaneous mouse model that delineates how the combination of inflammatory cytokine interleukin-27 (IL-27) signaling deficiency and mitogenic signaling (mutant p53R172H) in vivo, leads to bone loss in the vertebral bodies and ossification of the cartilage in the intervertebral discs. In this human disease-like mouse model, bone loss and pathogenic bone development are seen as early as 4 months of age in the absence of inflammatory aggregates in the enthesis or intervertebral disc.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. IL27RA-/- p53R172H/+ mice spontaneously develop bone loss and pathologic bone formation when compared with controls.
(A) Delineation of vertebral (V) and intervertebral disc (IVD) measurement (left). Representative micro-CT reconstruction (right) and (B) BMD measurement from the lumbar spine of aged WT, IL27RA-/-, p53R172H/+, and IL27RA-/- p53R172H/+ mice. (C) micro-CT reconstruction portraying abnormal bone growth in the spine of aged IL27RA-/- p53R172H/+ mice. (D) Photomicrograph of HE stained sections of the intervertebral disc of aged IL27RA-/- p53R172H/+ mice with rare inflammatory cells within the enthesis adjacent to the intervertebral discs. *, p< 0.05. Each dot represents an individual mouse.
Fig 2
Fig 2. IL27RA-/- p53R172H/+ mice spontaneously develop high incidence and low variation bone loss and ossification as early as age 4 months compared with controls.
(A) Representative micro-CT reconstruction and (B) BMD measurement from the lumbar spine of 2-, 4-, and 8-month- old WT, IL27RA-/-, p53R172H/+, and IL27RA-/- p53R172H/+ mice. (C) H&E stained images show normal intervertebral discs in WT and IL27RA-/- mice, and areas of pathologic ossification of the cartilage (black arrows) of the intervertebral disc around the nucleus pulposus in IL27RA-/- p53R172H/+ mice observed at 4 and 8 months of age. (D) BMD measurement of intervertebral discs of mice of various genotypes across time. *, p< 0.05. Each dot represents an individual mouse.
Fig 3
Fig 3. IL27RA-/- p53R172H/+ mice develop pathologies in other organs.
(A) Summary of the bone abnormalities in IL27RA-/- p53R172H/+ mice. (B and C) Chronic nephropathy with membranoproliferative glomerulonephritis (black arrows in B), atrophic glomeruli (black arrows in C), and dilated renal tubules with atrophic epithelium (green arrows in C). (D) Skin of the tail with chronic dermatitis and fibroplasia. (E) Chronic periosteitis and osteomyelitis of the vertebral body of tail. H&E stain, magnification 400x.
See this image and copyright information in PMC

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