Human gingival tissue-derived MSC suppress osteoclastogenesis and bone erosion via CD39-adenosine signal pathway in autoimmune arthritis

Abstract

Background Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. Method GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro . 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo . Finding GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro . GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro . Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo . Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo . Interpretation GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. Fund This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

“…The role of macrophages in RA joints is usually attributed to the correlation of macrophage numbers with radiological lesions but this is reinforced by the beneficial effect of targeting macrophages and the mediators they secrete 34,35 . In addition, macrophages differentiate into osteoclasts, resulting in bone destruction 36 . As reported previously, NR1D1 modulated macrophage polarization and SR9009 inhibited osteoclastogenesis 37 .…”

CD8+CD103+ iTregs Inhibit Chronic Graft-versus-Host Disease with Lupus Nephritis by the Increased Expression of CD39

“…Moreover, we and others have previously reported that CD39 regulates the immunosuppressive function of mesenchymal stem cells. 30 , 47 , 48 , 49 It is reasonable to make a hypothesis that CD39 may be a specific marker for CD8+CD103+ iTregs, which may also play an important role in the immunosuppressive function of CD8+CD103+ iTregs. CD39 and CD73 degrade extracellular ATP to adenosine together.…”

“…Entpd1 is responsible for coding CD39, which has a major impact on the equilibrium of ATP and adenosine. 30 , 31 We therefore hypothesized that CD39 plays a functional role in CD8+CD103+ iTregs.…”

Therapeutic Functions of Stem Cells from Oral Cavity: An Update

“…Also, the therapeutic potential of GMSCs have been also demonstrated in RA and other bone erosion related diseases; indeed, systemic infusion of GMSCs can significantly reduce the severity of experimental RA, and restore the balance of Th cell subsets via Fas ligand (FasL) and IL-10 secretion [175]. Transplantation of GMSCs into collagen-Induced arthritis (CIA) mice significantly attenuated the severity of arthritis and osteoclast activity, which in turn reduced bone erosion in vivo via anti-inflammatory CD39-CD73-adenosine signaling pathway [176].…”