FRI0367 Celastrol Inhibits Osteoclastogenesis and Bone Resorption in Rankl-Induced Raw264.7 via Nf-κB and MAPK Pathways and Attenuates Bone Erosion in Collagen-Induced Arthritis

Background

Celastrus have been long used to treat various inflammatory disorders including Rheumatoid arthritis (RA), SLE and Ankylosing Spondylitis in China. Celastrol is one of the main bioactive component of Celastrus. Previous study have reported both celastrus and celastrol can reduce the severity of clinical symptom in the rat adjuvant-induced arthritis (AA) model or human RA, supporting a potent anti-inflammatory activity of Celastrus. However, the direct role of Celastrol on osteoclast remain unknown.

Objectives

To examine the effects of Celastrol on osteoclastogenesis in osteoclast precursors RAW264.7 cell line and bone erosion in collagen-induced arthritis (CIA).

Methods

The roles of Celastrol on osteoclastogenesis in RAW264.7 was evaluated by tartrate-resistant acid phosphatase (TRAP) staining, Real-Time PCR and Western-blot. Activity of bone resorption was tested by pit formation assay in the presence or absence of Celastrol. The effects of Celastrol bone erosion in CIA mice was analyzed using histological analysis and Micro-CT.

Results

Celastrol inhibited RANKL-induced formation of TRAP+ multinucleated cells and bone-resorbing activity in a dose-dependent manner. The osteoclast formation was completely blocked with 0.3 μM of Celastrol. Celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors including Trap, Ctsk, Ctr, Mmp-9, NFATc1, c-Jun and c-Fos and phosphorylation of NF-kB and MAPK signals in RAW264.7. In CIA mice, administration of Celastrol markedly suppressed the arthritis score and reduced bone damage in the joints as demonstrated by histology and bone Micro-CT, which was accompanied by a decreased bone resorption marker of TRAP5b in serum and osteoclasts number in inflamed joint.

Conclusions

These findings revealed a directly inhibitory role of Celastrol on osteoclast formation and function, which is distinct from previous report, suggesting Celastrol provide a unique therapeutic strategy for RA and especially in light of preventing bone destruction.

Disclosure of Interest

None declared

DOI

10.1136/annrheumdis-2014-eular.3939