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p21 deficiency is susceptible to osteoarthritis through STAT3 phosphorylation
Conclusions: The lack of p21 has catabolic effects by regulation of aggrecan and MMP-13 expression through STAT3 phosphorylation in the cartilage tissue. p21 may function as a regulator of transcriptional factors other than the inhibitor of cell cycle progression in the cartilage tissue. Thus, the regulation of p21 may be a therapeutic strategy for the treatment of OA.
Source: Arthritis Research and Therapy - November 7, 2015 Category: Rheumatology Authors: Shinya HayashiTakaaki FujishiroShingo HashimotoNoriyuki KanzakiNobuaki ChinzeiShinsuke KiharaKoji TakayamaTomoyuki MatsumotoKotaro NishidaMasahiro KurosakaRyosuke Kuroda Source Type: research

Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1
Conclusions: Bach1 deficiency reduces the severity of OA-like changes. This may be due to maintenance of cartilage homeostasis and joint health by antioxidant effects through HO-1 and downregulation of extracellular matrix degrading enzymes. These results suggest that inactivation of Bach1 is a novel target and signaling pathway in OA prevention.
Source: Arthritis Research and Therapy - October 13, 2015 Category: Rheumatology Authors: Tsuyoshi TakadaShigeru MiyakiHiroyuki IshitobiYuya HiraiTomoyuki NakasaKazuhiko IgarashiMartin LotzMitsuo Ochi Source Type: research

Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mechanism
Conclusions: Cadherin-11 undergoes ectodomain shedding followed by regulated intramembrane proteolysis in synovial fibroblasts, triggered by a novel sheddase that generates extracelluar cadherin-11 fragments. Cadherin-11 fragments were enriched in RA synovial fluid, suggesting they may be a marker of synovial burden and may function to modify cadherin-11 interactions between synovial fibroblasts.
Source: Arthritis Research and Therapy - May 15, 2015 Category: Rheumatology Authors: Erika NossGerald WattsDavide ZoccoTracy KellerMalcolm WhitmanCarl BlobelDavid LeeMichael Brenner Source Type: research

Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novel mechanism of human osteoarthritis cartilage degeneration
IntroductionTo investigate if decreased histone deacetylase 4 (HDAC4) is associated with human osteoarthritis (OA) cartilage degeneration by releasing HDAC4 inhibition of runt-related transcription factor-2 (Runx2) resulting in increase of OA cartilage degeneration related genes. Methods: The mRNA and protein levels of HDAC4, Runx2, matrix metalloproteinase (MMP)-13, Indian hedgehog (Ihh) and type X collagen were detected by performing real time PCR (RT-PCR), western blotting and immunohistochemistry on specimens from human OA and normal cartilage. To further explore the mechanism of regulation of Runx2 and OA related gene...
Source: Arthritis Research and Therapy - November 26, 2014 Category: Rheumatology Authors: Kun CaoLei WeiZhiqiang ZhangLi GuoCongming ZhangYongping LiChangqi SunXiaojuan SunShaowei WangPengcui LIXiaochun Wei Source Type: research

Lysine specific demethylase 1-mediated demethylation of histone H3 lysine 9 contributes to interleukin 1beta-induced microsomal prostaglandin E synthase-1 expression in human osteoarthritic chondrocytes
Conclusion: These results indicate that H3K9 demethylation by LSD1 contributes to IL-1beta -induced mPGES-1 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA and possibly other arthritic conditions.
Source: Arthritis Research and Therapy - May 16, 2014 Category: Rheumatology Authors: Fatima El MansouriSalwa-Sarah NebbakiMohit KapoorHassan AfifJohanne Martel-PelletierJean-Pierre PelletierMohamed BenderdourHassan Fahmi Source Type: research

Endothelial protein C receptor associated invasiveness of rheumatoid synovial fibroblasts is likely driven by group V secretory phospholipase A2
Conclusion: Our results demonstrate that EPCR is overexpressed by RASF and mediates the aggressive behavior of RASF. This function of EPCR is contrary to its cytoprotective role in other settings, and is likely driven by sPLA2V.
Source: Arthritis Research and Therapy - February 5, 2014 Category: Rheumatology Authors: Meilang XueKaitlin ShenKelly McKelveyJuan LiYee-Ka ChanVicky HatzisLyn MarchChristopher LittleMichael TonkinChristopher Jackson Source Type: research

Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain
Conclusions: These results show that mechanical stress, IL-1beta and extracellular visfatin/NAMPT, all stimulated the expression and release of NGF by chondrocytes and thus suggest that the overexpression of visfatin/NAMPT and IL-1beta in OA joint and the increased mechanical loading of cartilage may mediate OA pain via the stimulation of NGF expression and release by chondrocytes.
Source: Arthritis Research and Therapy - January 20, 2014 Category: Rheumatology Authors: Emilie PecchiSabrina PriamMarjolaine GossetAudrey PigenetLaure SudreMarie-Charlotte LaiguillonFrancis BerenbaumXavier Houard Source Type: research

C/EBP homologous protein drives pro-catabolic responses in chondrocytes
IntroductionExcess C/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes. Methods: We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in alginate and subjected to sub-lethal biomechanical injury, and knee chondrocytes of human autopsy donors. We performed siRNA knockdown and transfection. Results: UPR activation was increased in human knee OA cartilage in situ, and in biomechanically injured cultured chondrocytes in vitro. In normal human chondrocyt...
Source: Arthritis Research and Therapy - December 19, 2013 Category: Rheumatology Authors: Matt HusaFreyr PeturssonMartin LotzRobert TerkeltaubRu Liu-Bryan Source Type: research

The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes
IntroductionExtracellular ATP (eATP) is released by articular chondrocytes under physiological and pathological conditions. High eATP levels cause pathologic calcification, damage cartilage, and mediate pain. We recently showed that stable over-expression of the progressive ankylosis gene product, ANK, increased chondrocyte eATP levels, but the mechanisms of this effect remained unexplored. The purpose of this work was to further investigate mechanisms of eATP efflux in primary articular chondrocytes and to better define the role of ANK in this process. Methods: We measured eATP levels using a bioluminescence-based assay i...
Source: Arthritis Research and Therapy - October 17, 2013 Category: Rheumatology Authors: Ann RosenthalClaudia GohrElizabeth Mitton-FitzgeraldMegan LutzGeorge DubyakLawrence Ryan Source Type: research

Linked decreases in Liver Kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes
IntroductionAMPK-activated kinase (AMPK) maintains cultured chondrocyte matrix homeostasis in response to inflammatory cytokines. AMPK activity is decreased in human knee osteoarthritis (OA) chondrocytes. Liver Kinase B1 (LKB1) is one of the upstream activators of AMPK. Hence, we examined the relationship between LKB1 and AMPK activity in OA and aging cartilages, and in chondrocytes subjected to inflammatory cytokine treatment and biomechanical compression injury, and performed translational studies of AMPK pharmacologic activation. Methods: We assessed activity (phosphorylation) of LKB1 and AMPKalpha in mouse knee OA cart...
Source: Arthritis Research and Therapy - July 24, 2013 Category: Rheumatology Authors: Freyr PeturssonMatthew HusaRon JuneMartin LotzRobert TerkeltaubRu Liu-Bryan Source Type: research

Shear stress modulates macrophage-induced urokinase plasminogen activator expression in human chondrocytes
Conclusions: These data support the hypothesis that uPA up-regulation stimulated by macrophages may play an active role in the onset of OA and in the shear stress protection against this induction.
Source: Arthritis Research and Therapy - April 18, 2013 Category: Rheumatology Authors: Chih-Chang YehShun-Fu ChangTing-Ying HuangHsin-I ChangHsing-Chun KuoYi-Chien WuChing-Hsiang HsiehChung-Sheng ShiCheng-Nan Chen Source Type: research