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Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells
  1. Ning Kong1,2,
  2. Qin Lan1,3,
  3. Maogen Chen1,
  4. Tina Zheng4,
  5. Wenru Su1,
  6. Julie Wang1,
  7. Ziyan Yang5,
  8. Ryan Park6,
  9. Grant Dagliyan6,
  10. Peter S Conti1,
  11. David Brand6,
  12. Zhongmin Liu3,
  13. Hejian Zou2,
  14. William Stohl1,
  15. Song Guo Zheng1,3
  1. 1Division of Rheumatology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  2. 2Division of Rheumatology, Huashan Hospital, Fudan University, Fudan, China
  3. 3Medicine Translation Center, Shanghai East Hospital, Tongji University, Shanghai, China
  4. 4Arcadia High School, Los Angeles, California, USA
  5. 5The Henry Samueli School of Engineering and Applied Science at UCLA, Los Angeles, California, USA
  6. 6Research Service, VA Medical Center, Memphis, Tennessee, USA
  1. Correspondence to Song Guo Zheng, Rheumatology Division, University of Southern California, Los Angeles, California 90033, USA; szheng{at}usc.edu, or Hejian Zou, Rheumatology Division, Fudan Unicersity, Shanghai, 200040, China

Abstract

Background Although natural regulatory T cells (nTregs) can suppress osteoclastogenesis, the role of TGF-β-induced CD4+Foxp3+ Tregs (iTregs) in osteoclastogenesis remains unknown.

Objective To determine the effects of iTregs on osteoclastogenesis in vitro and on bone erosion in vivo in collagen-induced arthritis (CIA).

Methods Osteoclastogenesis was induced in bone marrow CD11b+ cells with receptor activator of nuclear factor κ B (NF-κB) ligand (RANKL) and macrophage colony stimulating factor. Graded doses of Tregs were added to inhibit osteoclastogenesis. Transwell and antibody blockade experiments were performed to assess the roles for cell contact and soluble cytokines. NF-κB activation was determined by western blot. iTregs or nTregs were adoptively transferred to mice with CIA to assess in vivo effects on disease incidence and bone erosion, the latter determined by CT scanning.

Results Both nTregs and iTregs greatly suppressed osteoclastogenesis in vitro, but only iTregs sustained this effect when interleukin-6 was present. iTregs, but not nTregs, significantly suppressed development of CIA. Bone erosions in iTregs-treated mice were diminished compared with untreated mice or nTregs-treated mice. Treatment with iTregs, but not with nTregs, dramatically decreased NF-κB p65/p50 levels in osteoclasts in vitro and p65/50 and RANKL expression by synovial tissues in vivo.

Conclusion iTregs may be therapeutically beneficial in rheumatoid arthritis and related diseases associated with bone erosions.

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Footnotes

  • KN, LQ and CM contributed equally to this paper

  • Funding This work was supported in part by grants from the NIH R01 AR059103, R01 AR059193, R43 AI084359, ACR Within Our Reach Fund, Arthritis Foundation and Wright Foundation and China National Natural Science Foundation (No. 81072463).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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