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The role of myostatin (GDF-8) in chondrogenesis and fracture healing.

机译：肌生长抑制素（GDF-8）在软骨形成和骨折愈合中的作用。

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摘要

Myostatin (GDF-8), a member of the transforming growth factor beta superfamily, is a negative regulator of skeletal muscle growth and development. Loss of myostatin leads to an increase in fracture callus volume. Although myostatin is immediately expressed during the early phases of fracture healing, little is known about its source after injury, the time course of its expression, and its mechanism of action. We analyzed the temporal & spatial expression patterns of myostatin & its primary receptor (ActRIIB) using a fibular osteotomy in wildtype mice in a time-course immunohistochemical study. We showed that myostatin is highly expressed by the injured skeletal muscle fibers surrounding the site of bone fracture during the first 48 hours following osteotomy. Myostatin was also highly expressed by soft callus chondrocytes, cells that express ActRIIB and play a key role in fracture healing. These data reveal an autocrine mode of action of myostatin by chondrocytes, in addition to the muscle-derived paracrine source. Next, we examined the effect of myostatin on proliferation & chondrogenic differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs) as key steps in fracture healing. BMSCs were isolated from a GFP-Col2 reporter mouse using immunomagnetic beads, and purity was analyzed by high-speed flowcytometry. A high mass aggregate culture was treated in the presence or absence of recombinant myostatin in chondrogenic medium. Results showed that myostatin suppresses the proliferation, & chondrogenic differentiation of BMSCs by decreasing the production of Col2 (major cartilage collagen) and the expression of Sox5, and Sox9 (key chondrogenic transcription factors). We also showed that the negative effects of myostatin on BMSCs chondrogenic differentiation were associated with unique changes in the Wnt/beta-catenin signaling pathway, in particular down regulation of Wnt-5a. And finally, we assessed the direct role of myostatin in fracture healing using fibular osteotomy in wild type mice after receiving increasing doses of recombinant myostatin loaded in a biodegradable hydrogel injected directly into the open fracture site. MicroCT imaging and histological sections showed a dose-dependent decrease in fracture callus total bone volume, cartilage formation, and muscle regeneration with myostatin treatment. Together, these findings suggest that myostatin can regulate the initial differentiation of chondrogenic progenitors, and can represent a novel therapeutic target for management of orthopedic trauma where bone and muscle are damaged.
机译：Myostatin（GDF-8）是转化生长因子β超家族的成员，是骨骼肌生长发育的负调节剂。肌生长抑制素的损失导致骨折call的体积增加。尽管肌生长抑制素在骨折愈合的早期即刻表达，但对其损伤后的来源，表达的时间过程及其作用机理知之甚少。我们在一个时程免疫组织化学研究中使用腓骨截骨术在野生型小鼠中分析了肌肉生长抑制素及其主要受体（ActRIIB）的时空表达模式。我们显示，在截骨后的前4​​8小时内，骨折部位周围的受伤骨骼肌纤维高度表达了肌生长抑制素。肌生长抑制素也由软的愈伤组织软骨细胞高度表达，这些细胞表达ActRIIB并在骨折愈合中起关键作用。这些数据揭示了除肌肉来源的旁分泌来源外，软骨细胞对肌生长抑制素的自分泌作用方式。接下来，我们研究了肌生长抑制素对骨髓间充质干细胞（BMSCs）增殖和软骨分化潜能的影响，作为骨折愈合的关键步骤。使用免疫磁珠从GFP-Col2报告基因小鼠中分离BMSC，并通过高速流式细胞术分析纯度。在软骨生成培养基中存在或不存在重组肌生长抑制素的情况下处理高质量的团聚培养物。结果表明，肌生长抑制素通过降低Col2（主要软骨胶原蛋白）的产生以及Sox5和Sox9（关键软骨形成转录因子）的表达来抑制BMSC的增殖和软骨形成分化。我们还显示，肌生长抑制素对BMSCs软骨分化的负面影响与Wnt /β-catenin信号传导途径的独特变化有关，尤其是Wnt-5a的下调。最后，我们在接受增加剂量的重组肌生长抑制素装载在直接注入开放性骨折部位的可生物降解水凝胶中后，在野生型小鼠中使用腓骨截骨术评估了肌生长抑制素在骨折愈合中的直接作用。 MicroCT成像和组织学切片显示，用肌生长抑制素治疗后，骨折call的总骨量，软骨形成和肌肉再生呈剂量依赖性降低。总之，这些发现表明，肌生成抑制素可以调节软骨生成祖细胞的初始分化，并且可以代表骨和肌肉受损的整形外科创伤的新治疗靶标。

著录项

  • 作者

    Elkasrawy, Moataz N.;

  • 作者单位

    Medical College of Georgia.;

  • 授予单位 Medical College of Georgia.;
  • 学科 Biology Cell.;Health Sciences Osteopathic Medicine.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 123 p.
  • 总页数 123
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 I3;
  • 关键词

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