Background/Purpose:

Rheumatoid arthritis (RA) is an inflammatory disease that is characterized by chronic inflammation and bone destruction. Osteoclasts, which are bone-resorbing cells, are generally known to play a pivotal role in the pathogenesis of bone destruction in RA. Poly–γ-glutamic acid (γ-PGA), a natural polymer derived from Bacillus subtilis, has anti-inflammatory activity. It is mediated by suppressing differentiation of Th17 cells in asthma model. However, the effects of γ-PGA in RA osteoclast differentiation is unclear. Therefore, we evaluated whether γ-PGA prevents inflammation and joint damage of RA by regulating osteoclast differentiation in human and mice.

Methods:

We tested the inhibitory effect of γ-PGA on osteoclastogenesis in healthy human peripheral blood monocytes, RA synovial fluid macrophages, and mouse bone-marrow-derived macrophages (BMMs). The osteoclastogenesis was assessed by generation of TRAP-positive multinucleated cells and actin ring formation. We analyzed the expressions of essential genes and proteins for osteoclast differentiation by real-time PCR and western blot analysis. We observed whether treatment of γ-PGA efficiently reduces osteoclast formation and bone destruction in animal model of rheumatoid arthritis (collagen-induced arthritis [CIA] in DBA/1J mice).

Results:

Firstly, we showed that γ-PGA strongly inhibits osteoclast differentiation in normal PBMC-derived osteoclast precursors and RA synovial fluid macrophages. γ-PGA suppressed RANK mRNA and protein level by down-regulating of M-CSF receptor protein, which is required for RANK expression. Furthermore, we found that in vitro, treatment with γ-PGA suppressed osteoclastogenesis in wild-type (WT) mice, but the inhibition mechanism of γ-PGA was not TLR4-dependent since γ-PGA still inhibited osteoclast formation in TLR4-deficient mouse BMMs. Reflecting on these in vitro effects, oral administration of γ-PGA markedly reduced bone destruction in CIA mice. Histological analysis confirmed that γ-PGA prevented bone destruction and osteoclast formation in the bone tissues. In addition, treatment with γ-PGA also suppressed the expressions of IL-1β and TNF-α.

Conclusion:

Our results show that γ-PGA markedly suppresses osteoclastogenesis in human and mice. γ-PGA also reduces bone destruction, osteoclast formation, and inflammatory cytokines in animal model of RA. Thus, these data suggest that γ-PGA can be a good candidate for the therapeutic application of joint destruction in RA.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/poly-%ce%b3-glutamic-acid-inhibits-rankl-induced-osteoclast-differentiation-and-prevents-bone-destruction-in-rheumatoid-arthritis-human-and-cia-mouse-model/