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Deciphering the Molecular Mechanism Controlling Abnormal Angiogenesis in Ankylosing Spondylitis MSCs

Review of “SMAD‐specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis” from STEM CELLS by Stuart P. Atkinson

An abnormal increase in angiogenesis represents an important pathological feature of ankylosing spondylitis, a type of chronic, inflammatory arthritis that majorly impacts the pelvic bones and spine [1]. Interestingly, dysregulated angiogenesis of mesenchymal stem cells (MSCs) is closely related to inflammation and disrupted bone metabolism in patients with rheumatoid arthritis [2] and metastatic breast cancer [3], suggesting a possible link between MSCs and ankylosing spondylitis. Furthermore, the ubiquitin‐proteasome system also plays critical roles in both pathological angiogenesis [4] and the pathogenesis of ankylosing spondylitis [5], thereby adding another level of complexity.

In their new STEM CELLS article [6], researchers led by Huiyong Shen and Yanfeng Wu (The Eighth Affiliated Hospital of Sun Yat‐sen University, Shenzhen, Guangdong, China) brought these interrelated research lines together, and now show how SMAD Specific E3 Ubiquitin Protein Ligase 2 (SMURF2) [7] negatively regulates the stability of Pentraxin 3 (PTX3) [8], a soluble pattern‐recognition receptor with a high affinity for fibroblast growth factor 2 that has been linked to ankylosing spondylitis, to promote abnormal angiogenesis in MSCs derived from ankylosing spondylitis patients.

Ma et al. first confirmed that ankylosing spondylitis-MSCs (derived from the bone marrow) displayed increased angiogenesis when in vitro-cocultured with human umbilical vein endothelial cells (HUVECs) and following in vivo evaluation by Matrigel plug assay when compared to healthy counterparts. Given the potential importance of the ubiquitin‐proteasome system to this research, the authors evaluated the expression of the main components of this pathway and discovered the significant overexpression of several E3 ligases, including Smurf2. Interestingly, the downregulation of Smurf2 levels in ankylosing spondylitis-MSCs via short hairpin RNA expression readily inhibited the observed abnormal angiogenesis. Mechanistically, the authors found that activating transcription factor 4 (ATF4)‐induced endoplasmic reticulum stress [9] prompted the increased expression of Smurf2 in ankylosing spondylitis-MSCs, which then impacted angiogenesis by inducing the polyubiquitination and degradation of PTX3, which functions as a repressor of angiogenesis.

Overall, the authors reveal a new disease mechanism associated with ankylosing spondylitis pathogenesis – the overexpression of Smurf2 in MSCs leads to the degradation of PTX3, thereby promoting an increase in angiogenic activity. For more on the abnormal functions of tissue-resident stem cells during disease, stay tuned to the Stem Cells Portal!


References

  1. Appel H, Kuhne M, Spiekermann S, et al., Immunohistochemical analysis of hip arthritis in ankylosing spondylitis: Evaluation of the bone–cartilage interface and subchondral bone marrow. Arthritis & Rheumatism 2006;54:1805-1813.
  2. Mohanty ST, Kottam L, Gambardella A, et al., Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis. Arthritis Research & Therapy 2010;12:R149.
  3. Halpern JL, Kilbarger A, and Lynch CC, Mesenchymal stem cells promote mammary cancer cell migration in vitro via the CXCR2 receptor. Cancer Letters 2011;308:91-99.
  4. Rahimi N, The Ubiquitin-Proteasome System Meets Angiogenesis. Molecular Cancer Therapeutics 2012;11:538.
  5. Wright C, Edelmann M, diGleria K, et al., Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation and the ubiquitin-proteasome pathway. Annals of the Rheumatic Diseases 2009;68:1626.
  6. Ma M, Yang W, Cai Z, et al., SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis. STEM CELLS 2021;39:581-599.
  7. Zuscik MJ, Rosier RN, and Schwarz EM, Altered negative regulation of transforming growth factor β signaling in scleroderma: Potential involvement of SMURF2 in disease. Arthritis & Rheumatism 2003;48:1779-1780.
  8. Zhang X and Ding W, Association of Genetic Variants in Pentraxin 3 Gene with Ankylosing Spondylitis. Medical Science Monitor 2016;22:2911-6.
  9. Colbert RA, DeLay ML, Klenk EI, et al., From HLA-B27 to spondyloarthritis: a journey through the ER. Immunological Reviews 2010;233:181-202.