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THU0368 IL-22 Impact on Human Bone Marrow Mesenchymal Stem Cells Functions; A Novel Pathway That May Contribute To Aberrant New Bone Formation in Human SPA
  1. Y. El-Sherbiny1,2,
  2. A. El-Zayadi1,3,
  3. S. Churchman1,2,
  4. T. Baboolal1,
  5. R. Cuthbert1,
  6. J. El-Jawhari1,
  7. A. Alase1,
  8. A. Badawy3,
  9. E. Jones1,2,
  10. D. McGonagle1,2
  1. 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
  2. 2NIHR-Leeds Musculoskeletal and Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
  3. 3Department of Obstetrics and Gynecology, Mansoura University Hospitals, Mansoura, Egypt


Background The spondyloarthropathies (SpAs) including ankylosing spondylitis (AS) show a propensity for florid new bone formation following bouts of inflammation. However, in other skeletal diseases such as rheumatoid arthritis, inflammation predictably leads to diffuse bone loss and periarticular erosion.1 Anti-TNF therapies effectively alleviate spinal inflammation in SpA but fail to arrest the new bone formation.

SpAs are genetically and therapeutically linked to IL-23, which in turn regulates IL-22. it is a master regulator of stem cell niches in the intestine, liver, endometrium and skin2 but to the best of our knowledge, no data on its influence upon human osteoprogenitors or MSCs has been described.

Objectives We hypothesized that IL-22, a master regulator of stem cells in other niches, might also regulate mesenchymal stem cell (MSC) osteogenesis in an inflammation-dependent context.

Methods Bone marrow samples were obtained after informed consent (n=10), and MSCs isolated and culture expanded for 2–4 passages. Cells were analysed using flowcytometry for ISCT criteria and expression IL-22R ±IFNG and TNFa stimulation.

IL-22 effects were tested with and without inflammatory cytokines (IFNG and TNFa) on: MSC proliferation using colorimetric XTT assay, MSC migration using transwell migration assays, the expression of trascriptional factors of MSC adipo-, osteo- or chondro-genic potential using qRT-PCR, and on osteogenic differentiation assay evaluated by colorimetric calcium assay.

Results Interestingly, IL-22R expression was detected in MSCs intracellularly and showed a mean 1.8±0.12 fold increase post IFNG and TNFa stimulation.

MSC stimulation with combined IL-22, IFNG and TNFa but not single cytokines increased MSC proliferation (p=0.008) and migration (p=0.037) compared to unstimulated MSCs.

Osteogenic, adipogenic but not chondrogenic transcription factors were upregulated by IL-22 (p<0.05). Moreover, Inflammatory stimuli (IFNG+TNFa±IL-22) did not affect the chondro- and adipogenic transcription factors but did temper the increase of pro-osteogenic RUNX2. Mature bone markers, particularly BGLAP/osteocalcin were rarely detectable in the presence of inflammation. The inflammatory milieu also downregulated all tested chondrogenic markers ACAN, COL2A1 and COL10A1 compared to unstimulated and IL-22 stimulated MSCs.

Notably, MSC osteogenesis was enhanced following IL-22 exposure (p=0.031 for calcium production). The combination of IFNG and TNFa with or without IL-22 suppressed MSC osteogenesis (p=0.0313 for both).

Conclusions This is the first study to show that IL-22 is involved in MSC proliferation/migration in inflammatory environments with MSC osteogenesis occurring only in IFNG/TNFa absence. Given the genetic link with SpA, these physiological MSC bone responses need evaluation in pathological post-inflammation osteogenesis in human SpA.

  1. Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol 2014;57(1):28–37.

  2. Feng D, Kong X, Weng H, et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 2012;143(1):188–98 e7.

Disclosure of Interest None declared

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