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通过对细胞命运的精确局部控制来构建和维持关节。

Building and maintaining joints by exquisite local control of cell fate.

作者信息

Smeeton Joanna, Askary Amjad, Crump J Gage

机构信息

Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

出版信息

Wiley Interdiscip Rev Dev Biol. 2017 Jan;6(1). doi: 10.1002/wdev.245. Epub 2016 Sep 1.

Abstract

We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an "interzone" region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints. WIREs Dev Biol 2017, 6:e245. doi: 10.1002/wdev.245 For further resources related to this article, please visit the WIREs website.

摘要

我们身体的灵活性归功于骨骼之间复杂的关节连接。这些关节的形成需要多种组织类型的整合:缓冲关节骨骼的永久性软骨、包裹充满润滑液腔隙的滑膜,以及提供结构支撑的纤维囊和韧带。确定潜在的关节区域涉及在新生软骨凝聚物中建立关节祖细胞的“中间区域”,这是通过多种发育信号通路的激活剂和抑制剂之间的相互作用实现的。在中间区域内,BMP和TGFβ信号的严格调控可部分通过下游转录抑制因子和表观遗传调节剂来防止关节软骨细胞的肥大成熟。滑膜细胞随后通过促进润滑的基因表达以及诸如腔隙和附着点等复杂结构的形成而获得进一步的特化。虽然对小鼠和人类的基因研究已经发现了许多关节发育和稳态的调节因子,但斑马鱼的最新研究为理解关节定位和关节软骨细胞命运的调控提供了一种互补的简化方法。构建和维持关节的复杂性可能有助于解释为什么骨关节炎(人类最常见的疾病之一)的治疗方法仍然很少。一个主要挑战将是了解关节结构的发育异常以及发育基因在关节稳态中的产后作用如何导致关节出生缺陷和退行性疾病。WIREs发育生物学2017年,6:e245。doi:10.1002/wdev.245 有关本文的更多资源,请访问WIREs网站。

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