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      Control of chondrogenesis by the transcription factor Sox9

      Modern Rheumatology
      Informa UK Limited

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          Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

          Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.
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            The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage.

            To regenerate permanent cartilage, it is crucial to know not only the necessary conditions for chondrogenesis, but also the sufficient conditions. The objective of this study was to determine the signal sufficient for chondrogenesis. Embryonic stem cells that had been engineered to fluoresce upon chondrocyte differentiation were treated with combinations of factors necessary for chondrogenesis, and chondrocyte differentiation was detected as fluorescence. We screened for the combination that could induce fluorescence within 3 days. Then, primary mesenchymal stem cells, nonchondrogenic immortalized cell lines, and primary dermal fibroblasts were treated with the combination, and the induction of chondrocyte differentiation was assessed by detecting the expression of the cartilage marker genes and the accumulation of proteoglycan-rich matrix. The effects of monolayer, spheroid, and 3-dimensional culture systems on induction by combinations of transcription factors were compared. The effects of the combination on hypertrophic and osteoblastic differentiation were evaluated by detecting the expression of the characteristic marker genes. No single factor induced fluorescence. Among various combinations examined, only the SOX5, SOX6, and SOX9 combination (the SOX trio) induced fluorescence within 3 days. The SOX trio successfully induced chondrocyte differentiation in all cell types tested, including nonchondrogenic types, and the induction occurred regardless of the culture system used. Contrary to the conventional chondrogenic techniques, the SOX trio suppressed hypertrophic and osteogenic differentiation at the same time. These data strongly suggest that the SOX trio provides signals sufficient for the induction of permanent cartilage.
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              Transcriptional control of chondrocyte fate and differentiation.

              Chondrogenesis is an essential process in vertebrates. It leads to the formation of cartilage growth plates, which drive body growth and have primary roles in endochondral ossification. It also leads to the formation of permanent cartilaginous tissues that provide major structural support in the articular joints and respiratory and auditory tracts throughout life. Defects in chondrogenesis cause chondrodysostoses and chondrodysplasias. These skeletal malformation diseases account for a significant proportion of birth defects in humans and can dramatically affect a person's expectancy and quality of life. Chondrogenesis occurs when pluripotent mesenchymal cells commit to the chondrocyte lineage, and through a series of differentiation steps build and eventually remodel cartilage. This review summarizes and discusses our current knowledge and lack of knowledge about the chondrocyte differentiation pathway, from mesenchymal cells to growth plate and articular chondrocytes, with a main focus on how it is controlled by tissue patterning and cell differentiation transcription factors, such as, but not limited to, Pax1 and Pax9, Nkx3.1 and Nkx3.2, Sox9, Sox5 and Sox6, Runx2 and Runx3, and c-Maf. Copyright (c) 2005 Wiley-Liss, Inc.
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                Author and article information

                Journal
                Modern Rheumatology
                Modern Rheumatology
                Informa UK Limited
                1439-7595
                1439-7609
                January 02 2014
                June 2008
                January 02 2014
                June 2008
                : 18
                : 3
                : 213-219
                Article
                10.3109/s10165-008-0048-x
                7ac1e6e2-1b32-4824-a0f2-e4fadfd28bc2
                © 2008

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