Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis.

Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

Loss of mutual protection between human osteoclasts and chondrocytes in damaged joints initiates osteoclast-mediated cartilage degradation by MMPs.

Osteoclasts are multinucleated, bone-resorbing cells. However, they also digest cartilage during skeletal maintenance, development and in degradative conditions including osteoarthritis, rheumatoid arthritis and primary bone sarcoma. This study explores the mechanisms behind the osteoclast-cartilage interaction. Human osteoclasts differentiated on acellular human cartilage expressed osteoclast marker genes (e.g. CTSK, MMP9) and proteins (TRAP, VNR), visibly damaged the cartilage surface and released glycosaminoglycan in a contact-dependent manner. Direct co-culture with chondrocytes during differentiation increased large osteoclast formation (p < 0.0001) except when co-cultured on dentine, when osteoclast formation was inhibited (p = 0.0002). Osteoclasts cultured on dentine inhibited basal cartilage degradation (p = 0.012). RNA-seq identified MMP8 overexpression in osteoclasts differentiated on cartilage versus dentine (8.89-fold, p = 0.0133), while MMP9 was the most highly expressed MMP. Both MMP8 and MMP9 were produced by osteoclasts in osteosarcoma tissue. This study suggests that bone-resident osteoclasts and chondrocytes exert mutually protective effects on their 'native' tissue. However, when osteoclasts contact non-native cartilage they cause degradation via MMPs. Understanding the role of osteoclasts in cartilage maintenance and degradation might identify new therapeutic approaches for pathologies characterized by cartilage degeneration.

Activation of the Nrf2/HO-1 signaling pathway by dimethyl fumarate ameliorates complete Freund's adjuvant-induced arthritis in rats.

The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway has recently emerged as a novel therapeutic target in treating various diseases. Therefore, the present study aimed to assess the protective role of the Nrf2 activator, dimethyl fumarate (DMF) in the complete Freund's adjuvant (CFA)- induced arthritis model. DMF (25, 50, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered for 14 days. Pain-related tests, paw volume, and arthritic scores were measured weekly. Serum TNF-α, IL-1ß, cyclic citrullinated peptide (CCP), C-reactive protein (CRP), and rheumatoid factor (RF) levels were estimated. Nitrite, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and myeloperoxidase (MPO) levels were also evaluated. NF-κB, Nrf2, HO-1, and COX-2 levels were estimated in the joint tissue. DMF treatment exerted anti-arthritic activity by enhancing the nociceptive threshold, improving arthritis scores, and reducing paw edema. Also, DMF suppressed changes in oxidative stress markers and inflammatory mediators and enhanced Nrf2 and HO-1 levels in CFA-injected rats. These findings indicate that the anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.

d-Mannose suppresses osteoarthritis development in vivo and delays IL-1ß-induced degeneration in vitro by enhancing autophagy activated via the AMPK pathway.

Osteoarthritis (OA) is a heterogeneous disease that is consistently difficult to treat due to the complexity of the regulatory network involved in OA pathogenesis, especially in terms of cartilage degeneration. As a C-2 epimer of glucose, d-mannose can alleviate bone loss and repress immunopathology by upregulating regulatory T cells; however, the role of d-mannose in OA-related cartilage degeneration remains unknown. In this study, we investigated the chondroprotective effect of d-mannose in vitro and in vivo on OA. We found that incubating interleukin (IL)-1ß-treated rat chondrocytes with d-mannose restrained OA degeneration by elevating cell proliferation, strongly activating autophagy, reducing apoptosis, and downregulating catabolism. Additionally, oral gavage administration of d-mannose to monosodium iodoacetate (MIA)-treated rats revealed that a median (1.25 g/kg/day) rather than high or low dose of d-mannose suppressed OA progression and attenuated OA development based on lower macroscopic scores for cartilage, decreased histological scores for cartilage and synovium, strongly activated autophagy, and downregulated catabolism. In terms of a downstream mechanism, we showed that d-mannose might attenuate OA degeneration by activating autophagy in IL-1ß-treated rat chondrocytes by promoting the phosphorylation of 5' AMP-activated protein kinase (AMPK). Our in vitro findings revealed that d-mannose delayed IL-1ß-induced OA degeneration in rat chondrocytes by enhancing autophagy activation through the AMPK pathway. Furthermore, the in vivo results indicated that a median dose of d-mannose suppressed MIA-induced OA development. These results suggested that d-mannose exhibits chondroprotective effects and represents a potential disease-modifying drug and novel therapeutic agent for OA.

USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT-dependent manner.

Osteoarthritis is a chronic, systemic and inflammatory disease. However, the pathogenesis and understanding of RA are still limited. Ubiquitin-specific protease 13 (USP13) belongs to the deubiquitinating enzyme (DUB) superfamily, and has been implicated in various cellular events. Nevertheless, its potential on RA progression has little to be investigated. In the present study, we found that USP13 expression was markedly up-regulated in synovial tissue samples from patients with RA, and was down-regulated in human fibroblast-like synoviocytes (H-FLSs) stimulated by interleukin-1ß (IL-1ß), tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). We then showed that over-expressing USP13 markedly suppressed inflammatory response, oxidative stress and apoptosis in H-FLSs upon IL-1ß or TNF-α challenge, whereas USP13 knockdown exhibited detrimental effects. In addition, USP13-induced protective effects were associated with the improvement of nuclear factor erythroid 2-related factor 2 (Nrf-2) and the repression of Casapse-3. Furthermore, phosphatase and tensin homolog (PTEN) expression was greatly improved by USP13 in H-FLSs upon IL-1ß or TNF-α treatment, whereas phosphorylated AKT expression was diminished. In response to IL-1ß or TNF-α exposure, nuclear transcription factor κB (NF-κB) signaling pathway was activated, whereas being significantly restrained in H-FLSs over-expressing USP13. Mechanistically, USP13 directly interacted with PTEN. Of note, we found that USP13-regulated cellular processes including inflammation, oxidative stress and apoptotic cell death were partly dependent on AKT activation. Furthermore, USP13 over-expression effectively inhibited osteoclastogenesis and osteoclast-associated gene expression. The in vivo experiments finally confirmed that USP13 dramatically repressed synovial hyperplasia, inflammatory cell infiltration, cartilage damage and bone loss in collagen-induced arthritis (CIA) mice via the same molecular mechanisms detected in vitro. Taken together, these findings suggested that targeting USP13 may provide feasible therapies for RA.

PTH1-34 inhibited TNF-α expression and antagonized TNF-α-induced MMP13 expression in MIO mice.

This study aims to investigate the effects and mechanisms of parathyroid hormone [1-34] (PTH1-34) on TNF-α-stimulated mice chondrocytes, as well as cartilage from a meniscus injury induced osteoarthritis (MIO) mice model. The C57BL/6J mice received medial meniscectomy, and then administrated with PTH1-34. The results showed that PTH1-34 administration decreased secondary allodynia and the pain-related transcripts. The IHC, ELISA, Micro-CT imaging and histopathology analysis revealed the significantly improved subchondral plate thickness and bone porosity, the reduced pro-inflammatory cytokines in serum and joint fluid. In vitro, mice chondrocyte was treated with TNF-α or co-cultured with synovial cells. The results showed that TNF-α markedly upregulated the MMP13 expression, and the ERK1/2, NF-κB or PI3K signaling pathway inhibitors could reverse the induction effect of TNF-α on expression of MMP13 in chondrocytes. PTH1-34 alone has no effect on the expression of MMP13 and NF-κB signaling pathways, but the PTH1-34 could reverse the induction effect of TNF-α on MMP13 expression and NF-κB signaling pathway activation in chondrocytes. In addition, PTH1-34 administration inhibited the expression of TNF-α and MMP13, and chondrocyte viability, while the PKA repressor reversed the effect of PTH1-34 in chondrocytes co-cultured with synovial cells. In conclusion, PTH1-34 has an obvious analgesic and anti-inflammatory effect, inhibits the matrix synthesis and alleviates the progression of osteoarthritis. In vitro, PTH1-34 inhibited TNF-α expression and antagonized TNF-α-induced MMP13 expression via the PKA pathway and the NF-κB signaling pathways, respectively.

Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). AIM OF THE STUDY: This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. MATERIALS AND METHODS: The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1ß, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. CONCLUSION: The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway.

Long noncoding RNA ZFAS1 silencing alleviates rheumatoid arthritis via blocking miR-296-5p-mediated down-regulation of MMP-15.

Rheumatoid arthritis (RA), a chronic inflammatory disease, deprives patients' walking ability and reduces their life quality worldwide. Though recent studies have indicated the role of long noncoding RNA (lncRNA) ZFAS1 in several diseases, however, its role in RA remains uncharacterized. The present study aimed to unravel the the effect of ZFAS1 on RA. Herein, the RA mouse model and the human RA synoviocyte MH7A cell lines stimulated with TNF-α were established. ZFAS1 was next determined to be highly expressed in the mice with RA-like symptoms and TNF-α-stimulated MH7A cells while inhibiting ZFAS1 was demonstrated to promote proliferation and suppress apoptosis of MH7A cells. Furthermore, ZFAS1 knockdown exerted anti-inflammation effect in vitro and in vivo and reduced the arthritis index value. Moreover, RNA immunoprecipitation and dual-luciferase reporter assays identified the binding of ZFAS1 to microRNA (miR)-296-5p as well as the binding of miR-296-5p to matrix metalloproteinase-15 (MMP-15). Of note, ZFAS1 could bind miR-296-5p to up-regulate the expression of MMP-15. Our results from in vitro and in vivo experiments demonstrated silencing ZFAS1 mitigated RA-like symptoms such as inflammation and hyperplasia via miR-296-5p-dependent inhibition of MMP-15. Taken altogether, our study confirmed that ZFAS1 involved in RA progression by competitively binding to miR-296-5p and regulating MMP-15 expression.

Inhibition of PI3K/Akt/NF-κB signaling by Aloin for ameliorating the progression of osteoarthritis: In vitro and in vivo studies.

Osteoarthritis (OA) is a progressive and degenerative joint disease. Aloin is a bitter and yellow-brown-coloured compound from the Aloe plant and is allowed for use in foods as a "natural flavour". In our study, we examined the protective effects of Aloin on the inhibition of OA development as well as its underlying mechanism in both in vitro and vivo experiments. In in-vitro experiments, the protective effect of aloin on the anabolism and catabolism of the extracellular matrix (ECM) induced by IL-1 ß in chondrocytes by inhibiting the expression of pro-inflammatory factors, including TNF-α (p = 0.016), IL-6 (p = 0.006), iNOS (p = 0.001) and COX-2 (p = 0.006). Mechanistically, Aloin suppressed the IL-1ß-induced activation of the PI3K/Akt/NF-κB signalling pathway cascades. Moreover, molecular docking studies demonstrated that Aloin bound strongly to PI3K. In vivo, Aloin ameliorated the OA process in the destabilization of the medial meniscus (DMM) model. In summary, our findings demonstrate that Aloin ameliorates the progression of OA via the PI3K/Akt/NF-κB signalling pathways, which supports Aloin as a promising therapeutic agent for the treatment of OA.

The immunomodulatory role of PDEs inhibitors in immune cells: therapeutic implication in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA.

Gumiganghwal-tang ameliorates cartilage destruction via inhibition of matrix metalloproteinase.

ETHNOPHARMACOLOGICAL RELEVANCE: Kyung-Bang Gumiganghwal-tang tablet (GMGHT) is a standardized Korean Medicine that could treat a cold, headache, arthralgia and fever. Although GMGHT has been used for arthritis-related diseases including a sprain, arthralgia, unspecified arthritis and knee arthritis, there is no pre-clinical evidence to treat osteoarthritis (OA). This study determined the drug dosage and the mechanisms of GMGHT for OA. METHODS: OA was induced by intra-articular monoiodoacetic acid (MIA) injection in Sprague-Dawley rats. As calculated from the human equivalent dose formula, GMGHT was orally administered at the doses of 9.86, 98.6 and 986 mg/kg for 4 weeks. The arthritis score was performed by a blind test, and histological changes in articular cartilage were indicated by hematoxylin and eosin, Safranin O and toluidine blue staining. SW1353 chondrocytes were stimulated by interleukin (IL)-1ß recombinant to analyze the expressions of Type II collagen, matrix metalloproteinases (MMPs) and nuclear factor (NF)-κB. RESULTS: Rough and punctate surfaces of the femoral condyle induced by MIA, were recovered by the GMGHT treatment. The arthritis score was significantly improved in the 968 mg/kg of GMGHT-treated cartilage. Loss of chondrocytes and proteoglycan were ameliorated at the deep zone of the subchondral bone plate by the GMGHT administration in OA rats. The expression of Type II collagen was increased, while MMP-1, -3 and -13 levels were decreased in the GMGHT-treated SW1353 chondrocytes. In addition, the GMGHT treatment regulated NF-κB activation along with IL-6, transforming growth factor-ß and IL-12 production. CONCLUSIONS: GMGHT promoted the recovery of articular cartilage damage by inhibiting MMPs, accompanied with its anti-inflammatory effects in OA. GMGHT might be an alternative therapeutic treatment for OA.

Evaluation of metalloproteinases-2, -9, and -13 post photobiomodulation in mice talocrural joint.

The extracellular matrix (ECM) is the main constituent of connective tissue with structural and regulatory functions, stimulating cell differentiation and proliferation. Moreover, ECM is a dynamic structure in the constant remodeling process, which is controlled by a balance between metalloproteinases (MMPs) and their inhibitors (TIMPs). Photobiomodulation (PBM) is widely described in the literature and applied in clinical practices, although its effects on ECM have not yet been elucidated. Therefore, it was evaluated if PBM could alter ECM components, such as MMP-2, -9, -13, and TIMP-2 from mice talocrural joints. Mice were divided into 3 groups (n = 6): control, PBM 3 J cm-2, and PBM 30 J cm-2. A low-level laser (830 nm, 10 mW, 0.05 irradiated area, energy densities 3 J cm-2 and 30 J cm-2, the irradiation time of 15 and 150 s, respectively, continuous wave) was applied on the joint for 4 consecutive days. mRNA levels of metalloproteinases genes (MMP-2, MMP-9, and MMP-13), their regulator (TIMP-2), and protein expressions of MMP-13 and TIMP-2 were quantified. PBM can alter only mRNA relative levels of MMP-2 at 30 J cm-2 (p < 0.05), while MMP-9, MMP-13, and TIMP-2 mRNA relative levels did not demonstrate statistical differences for any of the groups (p > 0.05). Regarding protein expressions, MMP-13 demonstrated positive-labeled cells, only in articular cartilage, although the cell quantification did not demonstrate statistical differences when compared with the control group (p > 0.05). TIMP-2 did not present positive-labeled cells for any tissues evaluated. Our results indicate that PBM can alter MMP-2 mRNA relative level but cannot alter MMP-9, MMP-13, and TIMP mRNA relative levels. Moreover, both MMP-13 and TIMP-2 proteins were also unaltered after PBM.

microRNA-186 inhibition of PI3K-AKT pathway via SPP1 inhibits chondrocyte apoptosis in mice with osteoarthritis.

Chondrocyte apoptosis has been implicated as a major pathological osteoarthritis (OA) change in humans and experimental animals. We evaluate the ability of miR-186 on chondrocyte apoptosis and proliferation in OA and elucidate the underlying mechanism concerning the regulation of miR-186 in OA. Gene expression microarray analysis was performed to screen differentially expressed messenger RNAs (mRNAs) in OA. To validate the effect of miR-186 on chondrocyte apoptosis, we upregulated or downregulated endogenous miR-186 using mimics or inhibitors. Next, to better understand the regulatory mechanism for miR-186 governing SPP1, we suppressed the endogenous expression of SPP1 by small interfering RNA (siRNA) against SPP1 in chondrocytes. We identified SPP1 is highly expressed in OA according to an mRNA microarray data set GSE82107. After intra-articular injection of papain into mice, the miR-186 is downregulated while the SPP1 is reciprocal, with dysregulated PI3K-AKT pathway in OA cartilages. Intriguingly, miR-186 was shown to increase chondrocyte survival, facilitate cell cycle entry in OA chondrocytes, and inhibit chondrocyte apoptosis in vitro by modulation of pro- and antiapoptotic factors. The determination of luciferase activity suggested that miR-186 negatively targets SPP1. Furthermore, we found that the effect of miR-186 suppression on OA chondrocytes was lost when SPP1 was suppressed by siRNA, suggesting that miR-186 affected chondrocytes by targeting and depleting SPP1, a regulator of PI3K-AKT pathway. Our findings reveal a novel mechanism by which miR-186 inhibits chondrocyte apoptosis in OA by interacting with SPP1 and regulating PI3K-AKT pathway. Restoring miR-186 might be a future therapeutic strategy for OA.

uPA/uPAR signaling in rheumatoid arthritis: Shedding light on its mechanism of action.

Rheumatoid arthritis (RA) is a systemic and chronic autoimmune inflammatory disorder affecting multiple joints. Various cytokines, chemokines and growth factors synergistically modulate the joint physiology leading to bone erosion and cartilage degradation. Other than these conventional mediators that are well established in the past, the newly identified plasminogen activator (PA) family of proteins have been witnessed to possess a multifactorial approach in mediating RA pathogenesis. One such family of proteins comprises of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR)/soluble-type plasminogen activator receptor (suPAR). PA family of proteins are classified into two types namely: uPA and tissue type plasminogen activator (tPA). Both these subtypes have been implicated to play a key role in RA disease progression. However during RA pathogenesis, uPA secreted by neutrophils, chondrocytes, and monocytes are designated to interact with uPAR expressed on macrophages, fibroblast-like synoviocytes (FLS), chondrocytes and endothelial cells. Interaction of uPA/uPAR promotes the disease progression of RA through secretion of several cytokines, chemokines, growth factors and matrix metalloproteinases (MMPs). Moreover, uPA/uPAR initiates inflammatory responses in macrophages and FLS through activation of PI3K/Akt signaling pathways. Furthermore, uPAR plays a dual role in osteoclastogenesis under the presence/absence of growth factors like monocyte-colony stimulating factor (M-CSF). Overall, this review emphasizes the role of uPA/uPAR on various immune cells, signaling pathways and osteoclastogenesis involved in RA pathogenesis.

Matrix Metalloproteinases and Synovial Joint Pathology.

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes. These enzymes play a critical role in the destruction of articular cartilage in rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and the spondyloarthropathies. MMP gene expression is upregulated in these synovial joint pathologies in response to elevated levels of proinflammatory cytokines and soluble mediators such as tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, IL-17, and interferon-γ. These molecules are capable of activating the mitogen-activated protein kinase and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways by binding the cytokine to their respective receptors on immune cells, macrophages, chondrocytes, synoviocytes, and osteocytes leading to increased synthesis of MMPs. Biologic drugs and/or small-molecule inhibitors designed to block cytokine to cytokine receptor interactions or to selectively inhibit JAKs have clinical efficacy in RA, PsA, and ankylosing spondylitis which correlated with a reduction in MMPs. Although there are currently no OA-selective drugs, it is likely that such a drug would have to reduce MMP gene expression to have clinical efficacy.

Metalloproteinases in Rheumatoid Arthritis: Potential Therapeutic Targets to Improve Current Therapies.

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the destruction of joint tissues including cartilage and bone. Cartilage degradation is attributed to metalloproteinases (MPs) that belong to matrix metalloproteinase family and a disintegrin and metalloprotease with thrombospondin type 1 motifs produced by inflamed joint tissues. In addition, an enzyme that belongs to a disintegrin and metalloprotease family is also involved in release of inflammatory cytokines. Several highly selective inhibitors have been developed for MPs thought to play a role in RA pathogenesis and examining these inhibitors as potential drugs is becoming realistic. This chapter discusses recent reports on MPs in RA and their potential as a therapeutic target.

Anti-arthritic activity of 11-O-(4'-O-methyl galloyl)-bergenin and Crassula capitella extract in rats.

OBJECTIVES: Isolation and identification of phytochemicals of Crassula capitella (Thunberg), evaluation of the anti-arthritic potential of the extract and the major isolated compound; 11-O-(4'-O-methyl galloyl)-bergenin and underlying their mechanism on rat model of rheumatoid arthritis (RA). METHODS: Different fractions were subjected to column chromatography giving fourteen compound identified by mass and NMR spectroscopic techniques. RA was induced by intraplantar injection of complete Freund's adjuvant into the right hind paw of rats. Influence of tested samples in comparable to methotrexate on paw oedema, body weight gain, serum diagnostic markers, cartilage and bone degeneration enzymes, pro-inflammatory mediators and oxidative stress biomarkers in arthritic rats. KEY FINDINGS: Fourteen phenolic compounds were isolated and identified for the first time from C. capitella. The major compound identified as 11-O-(4'-O-methyl galloyl)-bergenin. Treatment of arthritic rats with extract or 11-O-(4'-O-methyl galloyl)-bergenin with the tested doses can reduce the progression and severity of RA. CONCLUSION: Crassula capitella is a new natural and abundant source for 11-O-(4'-O-methyl galloyl)-bergenin for resolving chronic inflammatory diseases as RA through antioxidant, anti-inflammatory and membrane stabilizing mechanism.

Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen-induced arthritis in mice.

OBJECTIVES: VX765, a potent and selective caspase-1 inhibitor, inhibits the release of IL-1, IL-18 and IL-33. In this study we investigated the effect of VX765 treatment on collagen-induced arthritis (CIA). METHODS: Twenty-four mice were randomly divided into three groups of 8: Normal (wild-type), CIA and VX765 (CIA with VX765 treatment) groups. Mice in the VX765 group received intraperitoneal injection of VX765 (100 mg/kg, twice daily) starting at the day of the booster immunisation (week 3) for a duration of 4 weeks. At the end of experiments (week 7), joints clinical scores, radiographic scores and histologic scores were evaluated. Serum IL-1ß, IL-18 and IL-33 levels were assessed by ELISA. RESULTS: VX765 prophylactic treatment significantly reduced joints clinical scores, suppressed bone marrow oedema and synovitis at the early stage of CIA, prevented bone erosion in progressive CIA, and decreased histologic scores and serum cytokine levels. CONCLUSIONS: VX765 prophylactic treatment ameliorated the severity and progression of CIA. These findings suggest that caspase-1 is a potential therapeutic target for RA treatment.

Baseline serum level of matrix metalloproteinase-3 as a biomarker of progressive joint damage in rheumatoid arthritis patients.

AIM: Matrix metalloproteinase-3 (MMP-3) plays a pivotal role in the destruction of bone and degradation of cartilage components in rheumatoid arthritis (RA). We aimed in this study to analyze the relation between baseline levels of MMP-3 and the progression of joint damage in RA. METHODS: Eighty-one untreated RA patients with joint symptoms for <1 year were evaluated at baseline and after 12 months as regards erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and plain X-ray of both hands and wrists. Baseline levels of MMP-3 were measured by enzyme-linked immunosorbent assay and magnetic resonance imaging (MRI) of hands/wrists was performed. Disease Activity Score (DAS28) and Health Assessment Questionnaire (HAQ) were performed at baseline evaluation and after 12 months. RESULTS: The baseline MMP-3 levels were significantly higher in the high-progression group compared with the low-progression one (95.75 ± 42.84 vs. 50.45 ± 12.83, P < 0.001). There was a positive correlation between baseline levels of MMP-3 and MRI erosion score and other baseline clinical parameters, except for HAQ and the van der Heijde modification of the Sharp scoring system (SvdH) scores, while after 12 months, there were high positive correlations between MMP-3 and SvdH score, as well as all parameters except for ESR. CONCLUSION: Serum baseline levels of MMP-3 are strong prognostic markers of disease activity, and act well as an early predictor of progressive joint damage in recent-onset RA disease.

Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction, disability, and decreased quality of life (QOL). Inhibition of Janus kinase (JAK) signaling ameliorates articular inflammation and joint destruction in animal models of RA, but its effects on behaviors indicating well-being are poorly understood. In this study, we evaluated the effect of JAK inhibition on spontaneous locomotor activity in rats with adjuvant-induced arthritis, a rodent model of RA. METHODS: Arthritis was induced in male Lewis rats by a single subcutaneous injection of Freund's complete adjuvant. The novel JAK inhibitor JTE-052 was orally administered for 7 days after the onset of arthritis. RESULTS: Induction of arthritis suppressed the spontaneous locomotor activity of the rats. Administration of JTE-052 completely improved the spontaneous locomotor activity, with partial reductions in articular inflammation and joint destruction. Hyperalgesia and motor functions were also improved, but the efficacy was not complete. However, serum interleukin (IL)-6 levels were completely decreased at 4 h after administration of the first dose of JTE-052. CONCLUSIONS: This study demonstrated that JAK inhibition improved the spontaneous locomotor activity of rats with adjuvant-induced arthritis, in association with amelioration of pain and physical dysfunction as a consequence of suppression of joint inflammation. Moreover, although further studies are needed, there was possible participation of IL-6 downregulation in the improvement of locomotor activity by JAK inhibition.