The chondroprotective effects of dopamine on osteoarthritis were possibly related to its ability to inhibit the NF-κB and JAK2/STAT3 signaling pathways.
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•Dopamine suppressed ...matrix-degrading protease production in OA chondrocytes.•Dopamine reduced the activation of the NF-κB pathway induced by IL-1β.•Dopamine exhibits chondroprotective effects by inhibiting the JAK2/STAT3 pathway activation.•Dopamine prevented the development of osteoarthritis in a mouse model.
The progressive loss of cartilage matrix and the breakdown of articular cartilage induced by inflammation play an essential role in osteoarthritis (OA) pathogenesis. Dopamine (DA) is a critical neurotransmitter that is not only involved in controlling exercise, emotion, cognition and neuroendocrine activity but also has anti-inflammatory effects. This study aimed to investigate the effects of DA on OA in vitro and in vivo.
OA progression was evaluated in a mouse model with surgically induced destabilization of the medial meniscus. Cartilage degradation and OA were analyzed using Safranin O/Fast Green staining. Additionally, qRT-PCR and Western blotting were applied to detect catabolic and anabolic factors involved in cartilage degeneration and underlying mechanisms in OA chondrocytes treated with Interleukin-1β.
In vitro, DA treatment inhibited the production of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13, while increasing type II collagen and glycosaminoglycan content. Mechanistically, DA reversed IL-1β-treated nuclear factor-kappa B activation and JAK2/STAT3 phosphorylation. Furthermore, DA suppressed the degradation of cartilage matrix and reduced Osteoarthritis Research Society International scores in the surgically induced OA models.
DA may be a novel therapeutic agent for OA treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•ACY-1215 inhibits inflammatory cytokines secretion in chondrocytes.•ACY-1215 suppressed matrix-degrading proteases production in chondrocytes.•ACY-1215 promotes the level of COL2A1 ...expression in IL-1β treated chondrocytes.•ACY-1215 exhibits chondroprotective effects by inhibiting STAT3 and NF-κB activation.
Cartilage degeneration is a basic pathological feature of osteoarthritis (OA), and there is growing evidence that it is associated with inflammation. ACY-1215, a selective HDAC6 inhibitor, has been reported to have anti-inflammatory effects. Here, we investigated the anti-inflammatory and chondroprotective effects of ACY-1215 in IL-1β-stimulated human primary chondrocytes and C28/I2 cells. The results suggested that ACY-1215 can markedly suppress the expression of inflammatory factors, including IL-1β and IL-6 in human primary chondrocytes and C28/I2 cells. Furthermore, ACY-1215 exerts potent chondroprotection through the amelioration of cartilage degradation by inhibiting the expression of matrix-degrading proteases, including MMP-1 and MMP-13 in chondrocytes. These effects may be related to ACY-1215 induced down-regulation of NF-κB and STAT3 pathways in OA chondrocytes. Taken together, our results show that ACY-1215 may be a potential and promising therapeutic drug for the management of OA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
Previous genome-wide association study showing a novel variant near
LSP1P3
was associated with knee osteoarthritis (KOA) in Caucasians. Replication study in different populations was ...essential to validate the association of novel susceptible genes with KOA. To our knowledge, there is a lack of study concerning the role of the
LSP1P3
gene in Chinese KOA patients. We aimed to determine the association between the novel variant near
LSP1P3
gene and the susceptibility of KOA in the Chinese population and to further investigate its relationship with the severity of KOA.
Methods
A total of 532 primary KOA patients who received treatment in our clinic center were included in the current study. Nine hundred twenty-seven age- and gender-matched healthy subjects were recruited as controls. The severity of KOA was graded according to the Kellgren-Lawrence (KL) grading system, with KL grade of 1 or 2 classified as mild KOA and KL grade of 3 or 4 classified as severe KOA. Three variants were genotyped using TaqMan SNP genotyping assay, including rs4867568 of
LSP1P3
gene, rs143383 of
GDF5
, and rs1558902 of
FTO
. The differences in terms of genotype and allele distributions between the cases and the controls were analyzed by the chi-square test.
Results
There were 215 male and 317 female patients with a mean age of 58.1 ± 7.2 years. According to the KL score, 172 (32.3%) patients had mild KOA and 360 (67.7%) had severe KOA. There were remarkably lower frequencies of allele T of rs4867568 and allele C of rs143383 in the patients than in the controls (31.5% vs. 36.0%,
p
= 0.01 for rs4867568; 24.6% vs. 28.7%,
p
= 0.02 for rs143383), with an OR of 0.82 and 0.81, respectively. As for rs1558902, no significant difference regarding the frequency of allele and genotype was found between the patients and the controls. Patients with severe KOA had remarkably lower incidence of genotype TT of rs4867568 than patients with mild KOA (6.7% vs. 12.2%,
p
= 0.04). There was significantly higher frequency of allele T in patients with mild KOA than in those with severe KOA (36.3% vs. 29.2%,
p
= 0.02, OR = 0.72).
Conclusions
The association of rs4867568 and rs143383 with KOA was successfully replicated in the Chinese Han population. Moreover, rs4867568 was found significantly associated with the severity of KOA. More studies are warranted to explore the functional role of rs4867568 in the development of KOA.
Key Points
• A novel variant near Lsp1p3 is associated with knee osteoarthritis.
• Baseline characteristics of the subjects.
• Comparison of the genotype and allele frequency of the Lsp1p3, GDF5, and FTO.
• Association of the Lsp1p3, GDF5, and FTO with KOA severity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•This is the first study to explore the possible role of HDAC6 in subchondral bone of OA.•ACY-1215 inhibits VEGF expression via PI3K/AKT pathway in OA osteoblasts.•ACY-1215 promotes apoptosis of OA ...osteoblasts.•This is the first study to investigate the protective effect of ACY-1215 in vivo by OA model mice.•This study provided a new evidence that HDAC6 inhibitor may be a potential therapeutic drug for OA.
Osteoarthritis (OA) is involved in these pathophysiological changes of articular cartilage, subchondral bone and synovium. As a selective HDAC6 inhibitor, Ricolinostat (ACY-1215) has demonstrated chondroprotective effects in OA. However, its efficacy remains unclear in subchondral bone. In this study, we found that the mRNA and protein levels of HDAC6 were elevated in human OA osteoblasts in vitro. PI3K/AKT signaling pathway was suppressed with downregulation of VEGF expression in osteoblasts after ACY-1215 treatment. ACY-1215 promoted apoptosis of OA osteoblast in a concentration-dependent manner, and the expression of apoptosis-related proteins was also changed by activating caspase pathway. Moreover, western blotting showed decreased expression of MMP9 and MMP13 in IL-1β-induced chondrocytes after co-culture with ACY-1215-stimulated osteoblasts. These data of immunohistochemistry and micro-CT from OA model mice also demonstrated the weak staining of MMPs in cartilage and prevention of aberrant subchondral bone formation after ACY-1215 injection. Therefore, high expression of HDAC6 in osteoblasts also contributed to the OA progression, and our study provided a new evidence that HDAC6 inhibitor may be a potential therapeutic drug for OA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteoarthritis (OA) is a prevalent bone and joint disease characterized by degeneration. The dysregulation between chondrocyte synthesis and breakdown is a key factor in OA development. Targeting the ...degenerative changes in cartilage tissue degradation could be a potential treatment approach for OA. Previous research has established a strong link between autophagy and the regulation of chondrocyte functions. Activating autophagy has shown promise in mitigating cartilage tissue degeneration. Currently, osteoarthritis treatment primarily focuses on symptom management, as there is no definitive medication to stop disease progression. Previous studies have demonstrated that luteolin, a flavonoid present in Chinese herbal medicine, can activate autophagy and reduce the expression of MMP1 and ADAMTS-5. This study utilized an in vitro osteoarthritis model with chondrocytes stimulated by IL-1β, treated with varying concentrations of luteolin. Treatment with luteolin notably increased the levels of synthesis factors Aggrecan and Collagen II, while decreasing the levels of decomposition factors MMP-1 and ADAMTS-5. Moreover, inhibition of autophagy by Chloroquine reversed the imbalances in chondrocyte activities induced by IL-1β. In an in vivo model of knee osteoarthritis induced by medial meniscal instability (DMM), luteolin was administered as a therapeutic regimen. After 12 weeks, knee cartilage tissues from mice were analyzed. Immunofluorescence and immunohistochemical staining revealed a decrease in P62 expression and an increase in Beclin-1 in the cartilage tissues. Additionally, cartilage wear in the knee joints of mice was alleviated by safranin O and fast green staining. Our study findings underscore the significant role of luteolin in effectively rebalancing chondrocyte activities disrupted by IL-1β. Our results strongly indicate that luteolin has the potential to be developed as a novel therapeutic agent for the treatment of osteoarthritis, offering promising prospects for future drug development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Several cellular and molecular processes participate in the pathologic changes of osteoarthritis (OA). However, the core molecular regulators of these processes are unclear, and no effective ...treatment for OA disease has been developed so far. ANGPTL2 is well known for its tissue remolding and pro-inflammation properties. However, the role of ANGPTL2 in osteoarthritis (OA) still remains unclear. To explore the expression level of ANGPTL2 in human OA cartilage and investigate the function of ANGPTL2 in human chondrocytes injury, qRT-PCR, western blot and immunohistochemistry were employed to investigate the expression of ANGPTL2 between human OA and normal cartilage samples. Next, human primary chondrocytes were treated with IL-1β to mimic OA progress in vitro, and the expression of ANGPTL2 were tested by qRT-PCR and western blot. Furthermore, the effect of ANGPTL2 in the expression of pro-inflammation cytokines (IL-1β, IL-6), proteolytic enzymes (MMP-1, MMP-13) and component of the cartilage matrix (COL2A1 and aggrecan) in human primary chondrocyte were explored by gain-of-function and loss-of-function methods. Finally, the nuclear factor kappa B (NF-κB) and p38/MAPK signaling pathways were also tested by western blot analysis. In this study, firstly, the expression level of ANGPTL2 was elevated both in human OA cartilage samples and IL-1β stimulated human chondrocytes. Secondly, ANGPTL2 upregulation promotes extracellular matrix (ECM) degradation and inflammation mediator production in human chondrocytes. Finally, ANGPTL2 activated the NF-κB and p38/MAPK signaling pathways via integrin α5β1. This study, for the first time, highlights that ANGPTL2 secreted by human chondrocytes plays a negative role in the pathogenesis of osteoarthritis, and it may be a potential therapeutic target in OA.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Scutellarin inhibits the expression of MMP1, MMP13 and ADAMTS-5.•Scutellarin inhibits the expression of wnt3a and frizzled7.•Scutellarin increases the expression of aggrecan and type II ...collagen.•Scutellarin attenuates Wnt/β-catenin and MAPK signaling induced by IL-1β.•Scutellarin ameliorates cartilage degradation in the animal osteoarthritis (OA) model.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•The expression levels of FzD7, Wnt3a and β-catenin are increased in human OA cartilage.•FzD7 CRD inhibits canonical Wnt3a/β-catenin signaling via binding and blocking Wnt3a.•FzD7 CRD ...increases anabolism gene synthesis and decreases the expression of catabolism genes in human chondrocytes.•FzD7 CRD ameliorates cartilage degeneration in a DMM mouse model.
Osteoarthritis (OA) is a chronic inflammatory joint disease without effective drugs. Frizzled 7 (FzD7) binds its ligand Wnt3a through an extracellular cysteine-rich domain (CRD) to transduce the canonical Wnt/β-catenin signaling pathway, which has been strongly implicated in OA pathogenesis. Effects of recombinant protein of FzD7 CRD on Wnt/β-catenin signaling and chondral destruction was evaluated in this study. Firstly, increased protein levels of FzD7, Wnt3a and β-catenin were detected in human OA cartilage implying that the canonical Wnt/β-catenin signaling mediated by Wnt3a and FzD7 executes an essential role in OA. Then we showed that FzD7 CRD antagonized the Wnt3a/β-catenin signaling pathway in a dose-dependent manner by binding Wnt3a. In addition, FzD7 CRD increased the expression of glycosaminoglycans (GAGs), Collagen II, aggrecan and reduced the expression of matrix metalloproteinase (MMP)-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) in Wnt3a-stimulated human chondrocytes. Furthermore, a single intra-articular injection of the FzD7 CRD was efficacious in destabilization of the medial meniscus (DMM) mouse OA model, significantly improving Osteoarthritis Research Society International (OARSI) histology scores compared to mice treated with PBS. The results indicate that the FzD7 CRD exhibits chondroprotective effects by binding Wnt3a to suppress the Wnt3a/β-catenin signaling. Targeting the FzD7 CRD may be a novel therapy for the treatment of OA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Keywords Osteoarthritis; ACY-1215; HDAC6; STAT3; NF-kappaB; Chondrocytes Highlights * ACY-1215 inhibits inflammatory cytokines secretion in chondrocytes. * ACY-1215 suppressed matrix-degrading ...proteases production in chondrocytes. * ACY-1215 promotes the level of COL2A1 expression in IL-1beta treated chondrocytes. * ACY-1215 exhibits chondroprotective effects by inhibiting STAT3 and NF-kappaB activation. Cartilage degeneration is a basic pathological feature of osteoarthritis (OA), and there is growing evidence that it is associated with inflammation. ACY-1215, a selective HDAC6 inhibitor, has been reported to have anti-inflammatory effects. Here, we investigated the anti-inflammatory and chondroprotective effects of ACY-1215 in IL-1beta-stimulated human primary chondrocytes and C28/I2 cells. The results suggested that ACY-1215 can markedly suppress the expression of inflammatory factors, including IL-1beta and IL-6 in human primary chondrocytes and C28/I2 cells. Furthermore, ACY-1215 exerts potent chondroprotection through the amelioration of cartilage degradation by inhibiting the expression of matrix-degrading proteases, including MMP-1 and MMP-13 in chondrocytes. These effects may be related to ACY-1215 induced down-regulation of NF-kappaB and STAT3 pathways in OA chondrocytes. Taken together, our results show that ACY-1215 may be a potential and promising therapeutic drug for the management of OA. Abbreviations OA, osteoarthritis; IL-1beta, interleukin-1beta; IL-6, interleukin-6; TNF-alpha, tumor necrosis factor-alpha; NSAIDs, non-steroidal anti-inflammatory drugs; COX-2, cyclooxygenase-2; HDAC6, histone deacetylase 6; STAT3, signal transducer and activator of transcription 3; NF-kappaB, nuclear factor-kappaB Author Affiliation: (a) Department of Orthopaedics, The Fourth Affiliated Hospital of Anhui Medical University, 372#Tun Xi Road, Hefei, 230032, Anhui, China (b) Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, 218#Ji Xi Road, Hefei, 230032, Anhui, China (c) School of Basic Medical Sciences, Anhui Medical University, 81#Mei Shan Road, Hefei, 230032, Anhui, China (d) Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, 17#Lu Jiang Road, Hefei, 230001, Anhui, China * Corresponding authors. Article History: Received 7 August 2018; Revised 26 October 2018; Accepted 6 November 2018 (footnote)1 Co-first authors. Byline: Chao Cheng (a,1), Wenshan Shan (b,1), Wei Huang (b,d,1), Zhenfei Ding (b), Guanjun Cui (b), Fuen Liu (b), Wei Lu (b), Jiegou Xu (c), Wei He weihe@ahmu.edu.cn (c,*), Zongsheng Yin anhuiyzs@126.com (a,*)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This work reports a facile method to prepare N-doped carbon sheets that are uniformly coated on the surface of CoNiO2@activated textile carbon (CS-CoNi@aTC). We used easily polymerized dopamine as ...the carbon precursor and hierarchical NiCo-LDH nanosheets grown on activated textile carbon as the flexible substrate. The subsequent thermal annealing treatment at 400 °C in a nitrogen atmosphere converts polydopamine into amorphous N-doped carbon and simultaneously decomposes the NiCo-LDH into CoNiO2. Both the thickness and mass loading of carbon sheets can be facilely controlled by changing the concentration of dopamine. Besides enhancing the areal capacitance of aTC by adding pseudocapacitance, these carbon sheets also significantly enhance the cycling stability of CoNiO2 through reinforcing the interfacial coupling of CoNiO2 nanosheets and carbon fibers. Acid etching of CoNiO2 leaves behind vertical carbon sheets connected on the aTC substrate (CS@aTC). An aqueous asymmetric supercapacitor (ASC) built with CS-CoNi@aTC and CS@aTC can exhibit remarkable cycling stability with 93% capacitance retention and 100% coulombic efficiency after continuous charging–discharging for 45 000 cycles. An assembled solid-state ASC delivers an areal capacitance of 284 mF cm−2 and a maximum volumetric energy density of 1.4 mW h cm−3 while exhibiting good flexibility and mechanical robustness.
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