Tier 3 — preclinical

Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice

Zheng W, Feng Z, You S, Zhang H, Tao Z, Wang Q, Chen H, Wu Y
International Immunopharmacology 2017 45:135-147

Bibliography

PubMed
PMID 28213268
DOI
10.1016/j.intimp.2017.02.009
Funding
Supported by the National Natural Science Foundation of China (81501907), Natural Science Foundation of Zhejiang Province (LY15H060008), and Wenzhou Science and Technology Bureau Foundation (Y20150063).
Competing interests
The authors declare no conflict of interest.

Study snapshot

DesignPrimary human osteoarthritic chondrocytes (from 4 OA patients undergoing knee arthroplasty) pretreated with fisetin +/- the SIRT1 inhibitor sirtinol before IL-1beta stimulation, measuring inflammatory mediators, MMPs and cartilage-matrix genes; paired with an in vivo mouse OA model induced by destabilisation of the medial meniscus (DMM), treated with oral fisetin (20 mg/kg/day, 8 weeks) and scored histologically (OARSI score, subchondral bone thickness, synovitis).
ModelPrimary human OA chondrocytes (in vitro) and C57BL/6 mouse DMM surgical osteoarthritis model (in vivo).
SampleChondrocytes from 4 human OA patients (2 men, 2 women, aged 55-67); mouse study used 4 groups of 10 mice each (sham, sham-fisetin, OA, OA+fisetin).
InterventionIn vitro: fisetin 1, 5 or 10 μM, +/- sirtinol 10 μM. In vivo: oral fisetin 20 mg/kg/day for 8 weeks after DMM surgery.
DurationIn vitro: 2 h fisetin pretreatment + 24 h IL-1beta stimulation. In vivo: 8 weeks post-surgery.
EndpointsNitric oxide, PGE2, IL-6, TNF-alpha (Griess reaction / ELISA); COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5 mRNA and protein (qRT-PCR, Western blot); SIRT1 protein expression and activity (Western blot, fluorometric assay); Sox-9, aggrecan, collagen-II mRNA and protein (qRT-PCR, immunofluorescence); OARSI histological score, subchondral bone plate thickness, synovitis score (in vivo)

What the study showed, in plain terms

Osteoarthritis involves both cartilage breakdown and low-grade joint inflammation, and this study asked whether fisetin could interrupt that process by activating SIRT1, a protein known to protect cartilage.

Chinese researchers treated cartilage cells taken directly from osteoarthritis patients with fisetin before exposing them to IL-1beta, an inflammatory trigger, and separately gave oral fisetin to mice with surgically induced knee osteoarthritis.

In human cartilage cells, fisetin blocked the IL-1beta-triggered rise in inflammatory mediators (NO, PGE2, IL-6, TNF-alpha) and cartilage-degrading enzymes (MMP-3, MMP-13, ADAMTS-5), preserved the cartilage-matrix genes Sox-9, aggrecan and collagen-II, and did so by activating SIRT1 — blocking SIRT1 with sirtinol cancelled fisetin's protective effect. In mice, 8 weeks of oral fisetin markedly reduced cartilage destruction (OARSI score), subchondral bone thickening and synovitis compared with untreated osteoarthritic mice.

Bottom line: solid preclinical evidence (human cells plus a mouse disease model, with a mechanistic blocker experiment) that fisetin protects cartilage via SIRT1 — a plausible mechanism for a musculoskeletal/joint-health use case, though this has not yet been tested in human osteoarthritis patients.

Key findings

Fisetin dose-dependently inhibited IL-1beta-induced NO, PGE2, IL-6, TNF-alpha, COX-2, iNOS, MMP-3, MMP-13 and ADAMTS-5 in primary human osteoarthritic chondrocytes, and preserved Sox-9, aggrecan and collagen-II expression, by activating SIRT1 (the effect was reversed by the SIRT1 inhibitor sirtinol). In a mouse surgical osteoarthritis model, 8 weeks of oral fisetin (20 mg/kg/day) significantly reduced OARSI cartilage-destruction scores, subchondral bone plate thickness and synovitis compared with untreated osteoarthritic mice.

What this study can and cannot tell us

Human chondrocytes were used in short-term culture (24 h stimulation), not in a human clinical trial; the in vivo efficacy data are from a surgically induced mouse model (DMM), which models mechanical OA but not all aspects of human disease (e.g., age-related or metabolic OA). Small human tissue donor sample (n=4). No data on oral bioavailability or joint-tissue drug levels achieved with the doses used.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology