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Sclareol exerts anti-osteoarthritic activities in interleukin-1?-induced rabbit chondrocytes and a rabbit osteoarthritis model.

ABSTRACT: Sclareol is a natural product initially isolated form Salvia sclarea which possesses immune-regulation and anti-inflammatory activities. However, the anti-osteoarthritic properties of sclareol have not been investigated. The present study is aimed at evaluating the potential effects of sclareol in interleukin-1? (IL-1?)-induced rabbit chondrocytes as well as an experimental rabbit knee osteoarthritis model induced by anterior cruciate ligament transection (ACLT). Cultured rabbit chondrocytes were pretreated with 1, 5 and 10 ?g/mL sclareol for 1 h and followed by stimulation of IL-1? (10 ng/mL) for 24 h. Gene expression of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, tissue inhibitors of metalloproteinase-1 (TIMP-1), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). MMP-3, TIMP-1, iNOS and COX-2 proteins were measured by Western blotting. Enzyme-linked immunosorbent assay (ELISA) was applied for nitric oxide (NO) and prostaglandin E2 (PGE2) assessment. For the in vivo study, rabbits received six weekly 0.3 mL sclareol (10 ?g/mL) intra-articular injections in the knees four weeks after ACLT surgery. Cartilage was harvested for measurement of MMP-1, MMP-3, MMP-13, TIMP-1, iNOS and COX-2 by qRT-PCR, while femoral condyles were used for histological evaluation. The in vitro results we obtained showed that sclareol inhibited the MMPs, iNOS and COX-2 expression on mRNA and protein levels, while increased the TIMP-1 expression. And over-production of NO and PGE2 was also suppressed. For the in vivo study, both qRT-PCR results and histological evaluation confirmed that sclareol ameliorated cartilage degradation. Hence, we speculated that sclareol may be an ideal approach for treating osteoarthritis.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC4440052 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Project description:BackgroundPaeonia suffruticosa is an important traditional Chinese herb used to treat osteoarthritis (OA) and oligostilbenes are the main active ingredient of the seeds of P. suffruticosa. The monomer trans-resveratrol of this species was demonstrated to have chondroprotective effects as a lead compound for the treatment of osteoarthritis, but it has not been applied due to its low efficacy.MethodsOligostilbenes were isolated by chromatography and were identified by NMR and HPLC. A rabbit osteoarthritis chondrocyte model was induced by interleukin-1? and was treated with individual drugs to systematically evaluate their effects. Cell Counting Kit 8 was used to test their effects on cell viability, calculate EC50 and plot a dose-response curve.Their effects on apoptosis were analyzed by Annexin V and PI staining, and the expression of chondrocyte-specific genes COL2A1, MMP13 and SOX9 was evaluated by real-time PCR.ResultsPaeonia suffruticosa seed extract could promote the cell viability of rabbit OA chondrocytes at low concentration and then ten oligostilbenes were isolated from it. Trans-oligostilbenes were better than their cis-forms, trimers and dimers were better than monomers for promoting the cell viability of rabbit osteoarthritis chondrocytes. None of the oligostilbenes was more effective than seed extract at the appropriate concentration; 1 ?M oligostilbenes all showed various anti-apoptotic effects. Trans-gnetin H showed the best effect on proliferation and inhibition of MMP13 expression on OA chondrocytes, while trans-viniferin was most effective in promoting the expression of COL2A1 and SOX9.ConclusionsTen oligostilbenes from P. suffruticosa seed all have certain protective effects on OA chondrocytes at low concentration. The trans-viniferin and some trimers have the potential to be further developed for the treatment of osteoarthritis because they were more effective than resveratrol and diacerein. The synergistic effect that may exist between oligostilbenes also warrants further research.

Project description:BackgroundAlthough increasing evidence has demonstrated that human dental pulp stem cells (hDPSCs) are efficacious for the clinical treatment of skeletal disorders, the underlying mechanisms remain incompletely understood. Osteoarthritis (OA) is one of the most common degenerative disorders in joints and is characterized by gradual and irreversible cartilaginous tissue damage. Notably, immune factors were newly identified to be closely related to OA development. In this study, we explored the modulatory effects of clinical-grade hDPSCs on osteoarthritic macrophages and their protective effects on cartilaginous tissues in OA joints.MethodsThe cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages were explored by phase contrast microscope, transmission electron microscopy, immunostaining, flow cytometry, quantitative polymerase chain reaction, and enzyme linked immunosorbent assay, respectively. Additionally, the factors and signaling pathways that suppressed macrophage activation by hDPSCs were determined by enzyme-linked immunosorbent assay and western-blotting. Furthermore, hDPSCs were administered to a rabbit knee OA model via intra-articular injection. Macrophage activation in vivo and cartilaginous tissue damage were also evaluated by pathological analysis.ResultsWe found that hDPSCs markedly inhibited osteoarthritic macrophage activation in vitro. The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages changed into less inflammatory status in the presence of hDPSCs. Mechanistically, we observed that hDPSC-derived hepatocyte growth factor and transforming growth factor β1 mediated the suppressive effects on osteoarthritic macrophages. Moreover, phosphorylation of MAPK pathway proteins contributed to osteoarthritic macrophage activation, and hDPSCs suppressed their activation by partially inactivating those pathways. Most importantly, injected hDPSCs inhibited macrophage activation in osteochondral tissues in a rabbit knee OA model in vivo. Further histological analysis showed that hDPSCs alleviated cartilaginous damage to knee joints.ConclusionsIn summary, our findings reveal a novel function for hDPSCs in suppressing osteoarthritic macrophages and suggest that macrophages are efficient cellular targets of hDPSCs for alleviation of cartilaginous damage in OA. hDPSCs treat OA via an osteoarthritic macrophages-dependent mechanisms. hDPSCs suppress the activation of osteoarthritic macrophages in vitro and in vivo and alleviate cartilaginous lesions in OA models.

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Sclareol exerts anti-osteoarthritic activities in interleukin-1?-induced rabbit chondrocytes and a rabbit osteoarthritis model.

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