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Abstract：
Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 flox/flox mice. and conducted histological and immunofluorescence analyses to investigate the phenotypes during skeletal development. In the Prx1cre line, we observed RS-like skeletal abnormities, including short stature and an arched skull. Additionally, we found inhibition of chondrocyte differentiation and proliferation. In the Osxcre line, loss of ROR2 in osteoblast lineage cells led to reduced osteoblast differentiation during both embryonic and postnatal stages. Furthermore, ROR2 mutant mice exhibited increased adipogenesis in the bone marrow compared to their littermate controls. To further explore the underlying mechanisms, bulk RNA-seq analysis of Prx1cre; Ror2 flox/flox embryos was performed, results revealed decreased BMP/TGF-β signaling. Immunofluorescence analysis further confirmed the decreased expression of p-smad1/5/8, accompanied by disrupted cell polarity in the developing growth plate. Pharmacological treatment using FK506 partially rescued the skeletal dysplasia and resulted in increased mineralization and osteoblast differentiation. By modeling the phenotype of RS in mice, our findings provide evidence for the involvement of mesenchymal progenitors as the cell origin and highlight the molecular mechanism of BMP/TGF-β signaling in skeletal dysplasia.
摘要：
遗传学研究表明Robinow综合征(RS),罕见的骨骼发育不良,是由ROR2突变引起的。然而,这种疾病的细胞起源和分子机制仍然难以捉摸。我们通过将Prx1cre和Osxcre与Ror2flox/flox小鼠杂交建立了条件敲除系统。并进行了组织学和免疫荧光分析，以研究骨骼发育过程中的表型。在Prx1cre行中，我们观察到RS样骨骼异常，包括身材矮小和拱形头骨。此外,我们发现抑制软骨细胞的分化和增殖。在Osxcre系列中，成骨细胞谱系细胞中ROR2的缺失导致胚胎和出生后成骨细胞分化降低。此外，与同窝对照相比，ROR2突变小鼠的骨髓脂肪生成增加。为了进一步探索潜在的机制，Prx1cre的大量RNA-seq分析；进行Ror2flox/flox胚胎，结果显示BMP/TGF-β信号降低。免疫荧光分析进一步证实了p-smad1/5/8的表达降低，伴随着发育中的生长板中细胞极性的破坏。使用FK506的药物治疗部分挽救了骨骼发育不良，并导致矿化和成骨细胞分化增加。通过对小鼠RS的表型建模,我们的研究结果为间叶祖细胞作为细胞来源的参与提供了证据，并强调了BMP/TGF-β信号传导在骨骼发育不良中的分子机制。
