Current state-of-the-art treatment of rheumatoid arthritis (RA) is not curative and is associated with considerable toxicity. Bone erosion and cartilage damage are the most severe complications of RA and the major reasons for pain and disability in this disease. They are also key targets that are resistant to current therapies. Substantial evidence now exists that mesenchymal stem cells (MSC) have regeneration ability and immunomodulatory functions that could contribute to treatment of autoimmune diseases. Nonetheless, it is unknown whether MSC, particularly those derived from gingival tissues (GMSC) can directly affect bone and cartilage protection. Based on our preliminary observations, we make a bold hypothesis that GMSC can directly inhibit the formation of osteoclasts and activities of inflamed synovial tissues and through these mechanisms can prevent bone erosion and cartilage damage in rheumatoid arthritis. The study will include two phases (R61 and R33) with three specific aims. For the R61 phase, specific aim 1 and 2 will test the hypothesis that GMSC suppress osteoclast differentiation and activities, as well as activation and function of inflamed synovial tissues in the in vitro and in vivo with collagen-induced arthritis (CIA) model and in the R33 phase (Specific aim 3) a further validation will be conducted using a humanized model. When successfully completed, this project will help us understand the characteristics of GMSC in protecting bone erosion and cartilage damage in autoimmune arthritis and may lead to a potential therapeutic strategy for RA and other human autoimmune diseases.

Public Health Relevance

Joints destruction characterized by bone erosion and cartilage damage is a mostly severe consequence and key reason that is resistant to current therapies in patients with rheumatoid arthritis. In the current study, we plan to use the collagen-induced arthritis and humanized animal models to study therapeutic effect of gingiva-derived mesenchymal stem cells (GMSC) on these models, particularly focusing on how GMSC suppress osteoclast differentiation/function and activities of inflamed synovial tissues in autoimmune arthritis, with the ultimate aim of improving therapeutic options for patients with RA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Project #
1R61AR073049-01
Application #
9468571
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Mao, Su-Yau
Project Start
2017-09-01
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Huang, Feng; Cao, Feng Lin; Zheng, Song Guo (2018) Update of humanized animal disease models in studying Graft-versus-host disease. Hum Vaccin Immunother 14:2618-2623
Huang, Feng; Liu, Zhong Ming; Zheng, Song Guo (2018) Updates on GMSCs Treatment for Autoimmune Diseases. Curr Stem Cell Res Ther 13:345-349
Lawless, Oliver J; Bellanti, Joseph A; Brown, Milton L et al. (2018) In vitro induction of T regulatory cells by a methylated CpG DNA sequence in humans: Potential therapeutic applications in allergic and autoimmune diseases. Allergy Asthma Proc 39:143-152
Fan, Xing-Liang; Zeng, Qing-Xiang; Li, Xin et al. (2018) Induced pluripotent stem cell-derived mesenchymal stem cells activate quiescent T cells and elevate regulatory T cell response via NF-?B in allergic rhinitis patients. Stem Cell Res Ther 9:170
Zou, Yaoyao; Xu, Siqi; Xiao, Youjun et al. (2018) Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation. J Clin Invest 128:4510-4524
Mo, Bi Yao; Guo, Xing Hua; Yang, Meng Ru et al. (2018) Long Non-Coding RNA GAPLINC Promotes Tumor-Like Biologic Behaviors of Fibroblast-Like Synoviocytes as MicroRNA Sponging in Rheumatoid Arthritis Patients. Front Immunol 9:702
Yang, Bo; Liu, Tingjun; Qu, Yang et al. (2018) Progresses and Perspectives of Anti-PD-1/PD-L1 Antibody Therapy in Head and Neck Cancers. Front Oncol 8:563
Peng, Wei-Xiang; Zhu, Shang-Ling; Zhang, Bai-Yu et al. (2017) Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling. Front Immunol 8:159
Chen, Weiqian; Xu, Zhenjian; Zheng, Yongjiang et al. (2017) A protocol to develop T helper and Treg cells in vivo. Cell Mol Immunol 14:1013-1016