Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis

Shang Ling Zhu, Jian Lin Huang, Wei Xiang Peng, Dan Chun Wu, Min Qi Luo, Qiu Xia Li, Zhao Xia Li, Xiao Xue Feng, Fang Liu, Ming Xia Wang, Wei Qian Chen, Nancy Olsen, Song Guo Zheng

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Abstract

Fibroblast-like synoviocytes (FLSs) contribute to synovial hyperplasia in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell proliferation. The objective of this study was to investigate the role of Smo in RA synoviocyte proliferation. FLSs were isolated from RA synovium. Shh signaling was studied using a Smo antagonist (GDC-0449) and small interfering RNA (siRNA) targeting the Smo gene in FLSs. Cell proliferation was quantified by using kit-8 assay and cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell cycle-related genes and proteins were detected by real-Time PCR and western blot. FLSs treated with GDC-0449 or Smo-siRNA showed significantly decreased proliferation compared to controls (P < 0.05). Incubation with GDC-0449 or transfection with Smo-siRNA resulted in a significant increase of G 1 phase cells compared to controls (P < 0.05). Cell cycle arrest was validated by the significant increase in cyclin D1 and E1 mRNA expression, decrease in cyclin-dependent kinase p21 mRNA expression in Smo-siRNA transfected cells (P < 0.05). Protein expression of cyclin D1 was also downregulated after Smo gene knockdown (P < 0.05). The results suggest that Shh signaling plays an important role in RA-FLSs proliferation in a Smo-dependent manner and may contribute to synovial hyperplasia. Targeting Shh signaling may help control joint damage in patients with RA.

Original languageEnglish (US)
Pages (from-to)214-222
Number of pages9
JournalCellular and Molecular Immunology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2017

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Zhu, S. L., Huang, J. L., Peng, W. X., Wu, D. C., Luo, M. Q., Li, Q. X., Li, Z. X., Feng, X. X., Liu, F., Wang, M. X., Chen, W. Q., Olsen, N., & Zheng, S. G. (2017). Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis. Cellular and Molecular Immunology, 14(2), 214-222. https://doi.org/10.1038/cmi.2015.67