Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Development. 2013 Jul;140(13):2680-90. doi: 10.1242/dev.093906. Epub 2013 May 29.
The assembly of the musculoskeletal system requires the formation of an attachment unit between a bone and a tendon. Tendons are often inserted into bone eminences, superstructures that improve the mechanical resilience of the attachment of muscles to the skeleton and facilitate movement. Despite their functional importance, little is known about the development of bone eminences and attachment units. Here, we show that bone eminence cells are descendants of a unique set of progenitors and that superstructures are added onto the developing long bone in a modular fashion. First, we show that bone eminences emerge only after the primary cartilage rudiments have formed. Cell lineage analyses revealed that eminence cells are not descendants of chondrocytes. Moreover, eminence progenitors were specified separately and after chondroprogenitors of the primary cartilage. Fields of Sox9-positive, Scx-positive, Col2a1-negative cells identified at presumable eminence sites confirm the identity and specificity of these progenitors. The loss of eminences in limbs in which Sox9 expression was blocked in Scx-positive cells supports the hypothesis that a distinct pool of Sox9- and Scx-positive progenitors forms these superstructures. We demonstrate that TGFβ signaling is necessary for the specification of bone eminence progenitors, whereas the SCX/BMP4 pathway is required for the differentiation of these progenitors to eminence-forming cells. Our findings suggest a modular model for bone development, involving a distinct pool of Sox9- and Scx-positive progenitor cells that form bone eminences under regulation of TGFβ and BMP4 signaling. This model offers a new perspective on bone morphogenesis and on attachment unit development during musculoskeletal assembly.
骨骼肌肉系统的装配需要在骨骼和肌腱之间形成一个附着单元。肌腱通常插入到骨隆起处，这些隆起结构提高了肌肉与骨骼附着的机械弹性，并促进了运动。尽管它们具有重要的功能，但人们对骨隆起和附着单元的发育知之甚少。在这里，我们表明，骨隆起细胞是一组独特祖细胞的后代，并且这些隆起结构是以模块的方式添加到正在发育的长骨上的。首先，我们表明，只有在初级软骨雏形形成之后，骨隆起才会出现。细胞谱系分析表明，隆起细胞不是软骨细胞的后代。此外，隆起祖细胞是在初级软骨的软骨祖细胞之后特异性地分化而来的。在假定的隆起部位， Sox9 阳性、 Scx 阳性、 Col2a1 阴性细胞的区域表明了这些祖细胞的身份和特异性。 Sox9 在 Scx 阳性细胞中表达被阻断的肢体中缺失了隆起，这支持了这样一种假设，即一个独特的 Sox9 和 Scx 阳性祖细胞池形成了这些隆起结构。我们证明了 TGFβ 信号通路对于骨隆起祖细胞的特化是必需的，而 SCX/BMP4 途径对于这些祖细胞分化为形成隆起的细胞是必需的。我们的研究结果表明，骨骼发育的一种模块化模型，涉及一个独特的 Sox9 和 Scx 阳性祖细胞池，这些祖细胞在 TGFβ 和 BMP4 信号通路的调节下形成骨隆起。该模型为骨骼形态发生和骨骼肌肉系统装配过程中附着单元的发育提供了一个新的视角。
