Université de Paris, Dental Faculty, Department of Oral Biology, Paris, France.
Centre de Recherche des Cordeliers, Université de Paris, Sorbonne Université, Inserm, Laboratory of Molecular Oral Pathophysiology, Paris, France.
J Dent Res. 2022 Jul;101(7):859-869. doi: 10.1177/00220345221074356. Epub 2022 Feb 11.
Craniofacial and jaw bones have unique physiological specificities when compared to axial and appendicular bones. However, the molecular profile of the jaw osteoblast (OB) remains incomplete. The present study aimed to decipher the bone site-specific profiles of transcription factors (TFs) expressed in OBs in vivo. Using RNA sequencing analysis, we mapped the transcriptome of confirmed OBs from 2 different skeletal sites: mandible (Md) and tibia (Tb). The OB transcriptome contains 709 TF genes: 608 are similarly expressed in Md-OB and Tb-OB, referred to as "OB-core"; 54 TF genes are upregulated in Md-OB, referred to as "Md-set"; and 18 TF genes are upregulated in Tb-OB, referred to as "Tb-set." Notably, the expression of 29 additional TF genes depends on their RNA transcript variants. TF genes with no previously known role in OBs and bone were identified. Bioinformatics analysis combined with review of genetic disease databases and a comprehensive literature search showed a significant contribution of anatomical origin to the OB signatures. Md-set and Tb-set are enriched with site-specific TF genes associated with development and morphogenesis (neural crest vs. mesoderm), and this developmental imprint persists during growth and homeostasis. Jaw and tibia site-specific OB signatures are associated with craniofacial and appendicular skeletal disorders as well as neurocristopathies, dental disorders, and digit malformations. The present study demonstrates the feasibility of a new method to isolate pure OB populations and map their gene expression signature in the context of OB physiological environment, avoiding in vitro culture and its associated biases. Our results provide insights into the site-specific developmental pathways governing OBs and identify new major OB regulators of bone physiology. We also established the importance of the OB transcriptome as a prognostic tool for human rare bone diseases to explore the hidden pathophysiology of craniofacial malformations, among the most prevalent congenital defects in humans.
颅面骨和颌骨与轴骨和附肢骨相比具有独特的生理特异性。然而，颌骨成骨细胞（OB）的分子特征仍然不完整。本研究旨在破译体内 OB 中表达的转录因子（TFs）的骨位特异性特征。使用 RNA 测序分析，我们绘制了来自 2 个不同骨骼部位的确认 OB 的转录组：下颌骨（Md）和胫骨（Tb）。OB 转录组包含 709 个 TF 基因：608 个在 Md-OB 和 Tb-OB 中表达相似，称为“OB-core”；54 个 TF 基因在 Md-OB 中上调，称为“Md-set”；18 个 TF 基因在 Tb-OB 中上调，称为“Tb-set”。值得注意的是，29 个额外的 TF 基因的表达依赖于它们的 RNA 转录变体。鉴定出了在 OB 和骨中以前未知作用的 TF 基因。生物信息学分析结合遗传疾病数据库的综述和全面的文献搜索表明，解剖起源对 OB 特征有显著贡献。Md-set 和 Tb-set 富含与发育和形态发生（神经嵴与中胚层）相关的特定部位的 TF 基因，这种发育印记在生长和稳态过程中持续存在。颌骨和胫骨的特定部位 OB 特征与颅面和附肢骨骼疾病以及神经嵴病、牙齿疾病和指畸形相关。本研究证明了一种新方法的可行性，该方法可以在 OB 生理环境中分离出纯 OB 群体并绘制其基因表达特征，避免了体外培养及其相关的偏差。我们的结果深入了解了控制 OB 的特定部位发育途径，并确定了新的 OB 骨骼生理学主要调节因子。我们还确定了 OB 转录组作为人类罕见骨骼疾病的预后工具的重要性，以探索颅面畸形的隐藏病理生理学，这是人类最常见的先天性缺陷之一。
