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Regulation of superficial zone protein in articular cartilage by TGF-beta signaling.

机译：TGF-β信号传导调节软骨中浅表层蛋白。

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摘要

Articular cartilage is an avascular tissue with limited innate potential for repair and regeneration that provides a low friction surface for joint movement (Reddi 2003). Superficial zone protein (SZP) has been identified as a boundary lubricant and stress dissipater within the synovial joint (Jay, Torres et al. 2007), encoded by the proteoglycan 4 gene (PRG4) (Ikegawa, Sano et al. 2000). SZP is a significant protein that plays a key role in the normal function of synovial joints; human and mouse mutants of the prg4 gene display precocious arthritis and arthropathies (Marcelino, Carpten et al. 1999; Rhee, Marcelino et al. 2005). Various aspects of SZP tribological function, protein distribution, mRNA expression and alternative splicing are regulated by the (Transforming Growth Factor Beta) TGF-beta signaling pathway as demonstrated in this dissertation.;The overall conclusion of this work is that the anatomical differences between anterior load-bearing locations of the femoral medial condyle M1 and M4 (posterior non-load bearing) with reference to SZP, that are modulated by differences in mechanical loading in vivo, can be replicated in vitro through the application of TGF-beta. The friction coefficient decreased in M4 explants following a two-day TGF-beta1 treatment and was attributed to the increased depth of staining of SZP in the near-surface region. The SZP level and the decrease in the friction coefficient of these explants are similar to those of the untreated M1 explants.;The M1 location demonstrated increased splicing out of exons 4 (containing the heparin-binding domain) and 5 compared to the non-load bearing location M4. Treatment with TGF-beta1 directly modulated the increased splicing out of exons 4 and 5 in explant and monolayer culture. In explants the response was rapid and is independent of new protein synthesis. Inhibition of Smad3 phosphorylation by SIS3 inhibited SZP protein expression and the increase in splicing out of exons 4 and 5 by TGF-beta1.;These observations support that regulation of SZP by mechanotransduction may be primarily controlled by the TGF-beta pathway, as this was sufficient to modulate the primary differences observed between the loaded and unloaded tissue.
机译：关节软骨是一种先天性的修复和再生潜力有限的无血管组织，可为关节运动提供低摩擦表面（Reddi 2003）。浅层蛋白（SZP）已被鉴定为滑膜关节内的边界润滑剂和应力消散剂（Jay，Torres et al。2007），由蛋白聚糖4基因（PRG4）编码（Ikegawa，Sano et al。2000）。 SZP是一种重要的蛋白质，在滑膜关节的正常功能中起关键作用。 prg4基因的人类和小鼠突变体表现出早熟性关节炎和关节病（Marcelino，Carpten et al。1999; Rhee，Marcelino et al。2005）。如本文所证明，SZP摩擦学功能，蛋白质分布，mRNA表达和选择性剪接的各个方面均受（转化生长因子β）TGF-β信号通路的调节。；这项工作的总体结论是前牙之间的解剖学差异股骨内侧con M1和M4（后部非承重）相对于SZP的承重位置受体内机械负荷差异的调节，可通过应用TGF-β在体外复制。经过两天的TGF-beta1处理，M4外植体的摩擦系数降低，这归因于SZP在近表面区域的染色深度增加。这些外植体的SZP水平和摩擦系数的降低与未处理的M1外植体的相似。; M1位置显示与外源相比，外显子4（包含肝素结合域）和5外显子的剪接增加。轴承位置M4。 TGF-beta1处理可直接调节外植体和单层培养中外显子4和5剪接的增加。在外植体中，反应迅速并且独立于新的蛋白质合成。 SIS3抑制Smad3磷酸化可抑制SZP蛋白表达以及TGF-beta1外显子4和5剪接的增加。这些观察结果表明，机械转导调控SZP可能主要受TGF-beta途径控制，因为这是足以调节在已加载和未加载的组织之间观察到的主要差异。

著录项

  • 作者

    DuRaine, Grayson Daniel.;

  • 作者单位

    University of California, Davis.;

  • 授予单位 University of California, Davis.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 115 p.
  • 总页数 115
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:25

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