Long bones of the appendicular skeleton are formed through endochondral ossification. Endochondral bone formation initiates with mesenchymal condensation, followed by the formation of a cartilage template which is replaced by bone. Fibroblast growth factor 9 (FGF9) regulates bone development. Fgf9-/- mice exhibit disproportionate shortening of proximal skeletal elements. Fgf9 missense mutations in mice and humans induce joint synostosis. Thus, FGF9 is critical for regulating bone length and joint formation. Conversely, mechanisms regulating bone width remain unclear. Here, we showed that the homozygous elbow knee synostosis (Eks) mutant mice harboring N143T mutation in Fgf9 have wide long bones at birth. We investigated the cellular and molecular mechanisms underlying the widened prospective humerus in Fgf9Eks/Eks embryos. Increased and expanded FGF signaling in concert with wider expression domain of Fgf receptor 3 (Fgfr3) during chondrogenic condensation of the humerus led to widened cartilage, which resulted in the formation of wider prospective humeri in neonatal Fgf9Eks/Eks mice. Increased and expanded FGF signaling during chondrogenic condensation led to increased density of chondrocytes of the humeri accompanied by increased proliferation of chondrocytes which express inappropriately higher levels of cyclin D1 in Fgf9Eks/Eks embryos. The results suggest that FGF9 regulates the width of prospective long bones by controlling the width of chondrogenic condensation.

中文翻译：

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小鼠成纤维细胞生长因子9 N143T突变导致长骨的广泛软骨凝集。

阑尾骨骼的长骨通过软骨内骨化形成。软骨内骨骼的形成始于间充质凝结，然后形成软骨模板，该模板被骨骼取代。成纤维细胞生长因子9（FGF9）调节骨骼发育。Fgf9-/-小鼠的近端骨骼元素缩短不成比例。Fgf9错义突变在小鼠和人类中引起关节突触。因此，FGF9对于调节骨长和关节形成至关重要。相反，调节骨宽度的机制仍不清楚。在这里，我们显示了在Fgf9中带有N143T突变的纯合子肘关节突触（Eks）突变小鼠出生时具有宽长骨。我们调查了Fgf9Eks / Eks胚胎中扩大的预期肱骨的细胞和分子机制。在肱骨软骨凝结过程中，FGF信号的增加和扩展与Fgf受体3（Fgfr3）的更广泛表达域协同作用，导致软骨变宽，从而导致新生Fgf9Eks / Eks小鼠形成更宽的前瞻性肱骨。软骨形成凝结过程中FGF信号的增加和扩展导致肱骨软骨细胞密度增加，并伴随着软骨细胞增殖的增加，而软骨细胞在Fgf9Eks / Eks胚胎中表达的cyclin D1水平过高。结果表明，FGF9通过控制软骨凝结的宽度来调节预期的长骨的宽度。这导致在新生Fgf9Eks / Eks小鼠中形成更宽的前瞻性肱骨。软骨形成凝结过程中FGF信号的增加和扩展导致肱骨软骨细胞密度增加，并伴随着软骨细胞增殖的增加，而软骨细胞在Fgf9Eks / Eks胚胎中表达的cyclin D1水平过高。结果表明，FGF9通过控制软骨凝结的宽度来调节预期的长骨的宽度。这导致在新生Fgf9Eks / Eks小鼠中形成更宽的前瞻性肱骨。软骨形成凝结过程中FGF信号的增加和扩展导致肱骨软骨细胞密度增加，并伴随着软骨细胞增殖的增加，而软骨细胞在Fgf9Eks / Eks胚胎中表达的cyclin D1水平过高。结果表明FGF9通过控制软骨凝结的宽度来调节预期的长骨的宽度。