Scutellarin ameliorates cartilage degeneration in osteoarthritis by inhibiting the Wnt/β-catenin and MAPK signaling pathways.
Osteoarthritis (OA) is a chronic inflammatory disease that is the basis of cartilage extracellular matrix degeneration and joint inflammation. Scutellarin is an herbal flavonoid glucuronide, isolated from the Chinese traditional herb Erigeron breviscapus, has been reported to have anti-inflammatory effect. Here, we showed that Scutellarin could inhibit inflammation and protects cartilage from degeneration in vitro and in vivo. Scutellarin downregulate the mRNA and protein expression of MMP1, MMP13, and ADAMTS-5, Wnt3a, Frizzled7 and promote the expression of Collagen II and Aggrecan. Moreover, scutellarin inhibit the migration of β-catenin and phosphorylation of p38 into the nucleus, which may relate to the mediation of the Wnt/β-catenin and MAPK signaling pathway. Furthermore, scutellarin significantly inhibit the cartilage degradation of DMM-induced OA mice by safranin-O and fast green staining. In conclusion, our study indicates that scutellarin may be a potential drug for the treatment of OA.
Liu F
，Li L
，Lu W
，Ding Z
，Huang W
，Li YT
，Cheng C
，Shan WS
，Xu J
，He W
，Zhanghui
，Yin Z
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Jiawei Yanghe decoction ameliorates cartilage degradation in vitro and vivo via Wnt/β-catenin signaling pathway.
Jiawei Yanghe decoction (JWYHD) is a Traditional Chinese Medicine (TCM) formula for the treatment of osteoarthritis (OA), however the underlying mechanisms of action of JWYHD in OA are not fully explored. This study investigates how JWYHD protects cartilage from degradation via Wnt/β-catenin signaling pathway. The chondroprotective and anti-inflammatory effect of JWYHD on chondrocytes in vitro and on MIA-induced OA rat model in vivo were investigated. In vitro, JWYHD increased the chondrocyte viability against interleukin (IL)-1β-induced chondrocytes apoptosis and preserved glycosaminoglycans in the extracellular matrix. JWYHD promoted chondrocyte viability against apoptosis, decreased MMP-3, MMP-13, Caspase-3, Caspase-9 via Wnt/β-catenin signaling pathway in both IL-1β-induced and Licl-induced chondrocytes. The qRT-PCR and western blot results showed that mRNA and protein expressions of Wnt signaling pathway related genes β-catenin and CyclinD1, apoptosis related genes Casapase-3 and Caspase-9, collagen degradation related genes Metalloproteinase (MMP)-3 and MMP-13 were up-regulated, and Col2a1 was down-regulated on IL-1β-induced chondrocytes. Treatment with JWYHD reversed these effects in a dose-dependent manner. Licl was used as Wnt/β-catenin signaling pathway activator in chondrocytes to determine the molecular mechanisms. Activation of Wnt signaling pathway by Licl up-regulated β-catenin, CyclinD1, Axin2, Caspase-3, Caspase-9, MMP-3, MMP-13 and IL-1β. These effects were blocked by JWYHD treatment. Furthermore, 75 Sprawl-Dawley rats were used to verify the results obtained in vitro. A total of 75 rats were randomly divided into the control group (no MIA-induced OA, received intragastric administration of an equivalent amount of saline), the OA group (MIA-induced OA, received intragastric administration of an equivalent amount of saline), and the JWYHD treatment group (MIA-induced OA, received intragastric administration of an equivalent amount of various concentrations of JWYHD at 1.4/2.7/5.5 g/kg). After 8 weeks of administration, all rats were sacrificed. JWYHD decreased the MIA-induced up-regulation of β-catenin, CyclinD1, Caspase-3, Caspase-9, MMP-3 and MMP-13 protein expressions in cartilage. It was also demonstrated that JWYHD decreased serum and synovium pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α in MIA-induced OA rats and ameliorated the cartilage degradation. Histopathological staining, macroscopic observation and micro-CT scan with 3-dimension remodeling showed a cartilage protective effect of JWYHD. In conclusion, JWYHD possess multiple capabilities including preventing chondrocyte apoptosis, preserving integrity of extracellular matrix and anti-inflammatory effect in the treatment of OA both in vitro and in vivo.
Xia H
，Cao D
，Yang F
，Yang W
，Li W
，Liu P
，Wang S
，Yang F
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Emodin ameliorates cartilage degradation in osteoarthritis by inhibiting NF-κB and Wnt/β-catenin signaling in-vitro and in-vivo.
The overproduction of MMPs (matrix metalloproteinases) and members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family plays an important role in the pathogenesis of osteoarthritis (OA). The potential of selective MMPs or ADAMTS inhibitors as chemopreventive agents for OA has been demonstrated in several studies. In this study, we investigated the protective effects of emodin (1,3,8-trihydroxy-6-methylanthaquinone), isolated from the root of Rheum palmatum L., in the inhibition of MMP and ADAMTS expression in both rat chondrocytes and an animal model of OA. The expression of MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, aggrecan, and collagen II mRNA and protein in interleukin-1beta (IL-1β)-induced rat chondrocytes was followed by quantitative real-time PCR and western blot. The activation of the NF-κB and Wnt/β-catenin pathways by IL-1β was assessed by western blot. The in vivo effects of emodin were evaluated by intra-articular injection in rats in an experimental model of OA induced by anterior cruciate ligament transection. Emodin dose-dependently down-regulated the expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 at both the mRNA and protein level in IL-1β-stimulated rat chondrocytes. In addition, the IL-1β-induced activation of NF-κB and Wnt signals was attenuated by emodin, as determined by western blotting. The intra-articular injection of emodin in a rat OA model ameliorated OA progression, as determined in morphological and histological analyses in vivo. Taken together, our findings demonstrate that emodin is a promising therapeutic agent for the prevention and treatment of OA.
Ding QH
，Ye CY
，Chen EM
，Zhang W
，Wang XH
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Inhibition of cartilage degradation and suppression of PGE(2) and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis.
Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. The aim of this study was to determine whether oral consumption of PFE inhibits disease progression in rabbits with surgically induced OA.
OA was surgically induced in the tibiofemoral joints of adult New Zealand White rabbits. In one group, animals were fed PFE in water for 8 wk postsurgery. In the second group, animals were fed PFE for 2 wk before surgery and for 8 wk postsurgery. Histologic assessment and scoring of the cartilage was per Osteoarthritis Research Society International guidelines. Gene expression and matrix metalloproteinases (MMP) activity were determined using quantitative reverse transcriptase polymerase chain reaction and fluorometric assay, respectively. Interleukin (IL)-1 β, MMP-13, IL-6, prostaglandin (PG)E2, and type II collagen (COL2A1) levels in synovial fluid/plasma/culture media were quantified using enzyme-linked immunosorbent assay. Expression of active caspase-3 and poly (ADP-ribose) polymerase p85 was determined by immunohistochemistry. Effect of PFE and inhibitors of MMP-13, mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB was studied in IL-1 β-stimulated rabbit articular chondrocytes.
Safranin-O-staining and chondrocyte cluster formation was significantly reduced in the anterior cruciate ligament transaction plus PFE fed groups. Expression of MMP-3, MMP-9, and MMP-13 mRNA was higher in the cartilage of rabbits given water alone but was significantly lower in the animals fed PFE. PFE-fed rabbits had lower IL-6, MMP-13, and PGE2 levels in the synovial fluid and plasma, respectively, and showed higher expression of aggrecan and COL2A1 mRNA. Significantly higher numbers of chondrocytes were positive for markers of apoptosis in the joints of rabbits with OA given water only compared with those in the PFE-fed groups. PFE pretreatment significantly reduced IL-1 β induced IL-6 and MMPs expression in rabbit articular chondrocytes. These effects were also mimicked using MMP-13, MAPK, and NF-κB inhibitors in IL-1 β-stimulated rabbit chondrocytes. In an in vitro activity assay, PFE blocked the activity of MMP-13. Like MAPK and NF-κB inhibitors, PFE was also effective in inhibiting IL-1 β-induced PGE2 production in rabbit chondrocytes. PFE also reversed the inhibitory effect of IL-1β on COL2A1 mRNA and protein expression in IL-1 β-stimulated rabbit chondrocytes.
The present data highlight the chondroprotective effects of PFE oral consumption in a model of posttraumatic OA and suggest that PFE-derived compounds may have potential value in the management of OA.
Akhtar N
，Khan NM
，Ashruf OS
，Haqqi TM
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