Hedgehog信号通路在下颌骨发育过程中作用机制的研究进展

Research progress on the mechanism of the Hedgehog signaling pathway during mandibular development

下颌骨的发育来源及发育过程均与全身其他骨骼有着显著差异,其发育异常会导致各种骨相关疾病,严重影响了患者的生活质量。近年来Hedgehog信号通路在骨骼发育过程中的作用越来越受到关注。Hedgehog基因包括Sonic Hedgehog(Shh)、Indian Hedgehog(Ihh)和Desert Hedgehog(Dhh)3种亚型,其中Shh及Ihh可通过多种途径参与骨代谢调节,Shh主要参与肢体发育过程,而Ihh主要是在软骨内成骨过程中发挥关键作用。Hedgehog信号通路包括Hedgehog信号蛋白配体、Patched(Ptch)受体、Smoothed(Smo)受体、核内转录因子神经胶质瘤相关癌基因同源蛋白(glioma-associated oncogene homologue,Gli)和下游靶基因等。典型Hedgehog信号通路由Gli激活调控,而非典型Hedgehog信号主要由Ptch、Smo等调控。Shh在早期脊椎动物胚胎形成过程中调控多种生物学行为,如器官的分化、神经干的形成、干细胞的分化增殖、四肢骨骼发育以及牙胚发育等;在骨细胞分化过程中,Shh、Ptch1和Gli1在成骨细胞中均有表达,进一步促进骨髓间充质干细胞向成骨细胞和软骨细胞分化。Ihh对骨骼生长发育以及稳态维持具有不可或缺的功能作用,参与膜内骨领的形成、软骨细胞的增殖和成熟,Ihh在成熟的颅骨成骨细胞中表达,其可作为促成骨因子调控Ptch和骨形态发生蛋白(bone morphogenetic protein,BMP)的表达来诱导膜内骨化过程;脑和肌肉ARNT样蛋白1(brain and muscle ARNT-like 1,BMAL1)可通过与Ptch1和Ihh结合,调节Hedgehog信号通路,在颞下颌关节的软骨形成和软骨内成骨过程中发挥关键作用;而Hedgehog信号激活剂可以改善由BMAL1缺失引起的下颌骨骨量减少。Hedgehog信号失调会对骨发育过程产生重大影响,并导致一系列骨疾病如骨发育异常、骨折、骨质疏松和骨关节炎。然而,Hedgehog信号通路与下颌骨疾病的相关作用机制尚未完全阐明,未来研究可进一步探讨Hedgehog信号作为治疗下颌骨发育相关疾病的潜在靶点。

The source and process of mandible development are significantly different from those of other bones in the body,and abnormal development can lead to various bone-related diseases,seriously affecting the quality of life of patients.In recent years,the role of the Hedgehog signaling pathway in bone development has received increasing attention.The Hedgehog gene includes three subtypes:Sonic Hedgehog(Shh),Indian Hedgehog(Ihh),and Desert Hedgehog(Dhh).Shh and Ihh can participate in bone metabolism regulation through various pathways,with Shh primarily involved in limb development and Ihh playing a key role in endochondral osteogenesis.The Hedgehog signaling pathway includes Hedgehog signaling protein ligands,Patched(Ptch)receptors,Smoothed(Smo)receptors,nuclear transcription factors,glioma-associated oncogene homologues(Gli),and downstream target genes.The activation of typical Hedgehog signaling pathways requires the involvement of Gli,whereas atypical Hedgehog signaling is mainly regulated by Ptch,Smo,and others-Shh regulates various biological behaviors during early vertebrate embryogenesis,such as organ differentiation,neural stem formation,stem cell differentiation and proliferation,limb bone development,and tooth germ development.During the process of bone cell differentiation,Shh,Ptch1,and Gli1 are expressed in osteoblasts,further promoting the differentiation of bone marrow mesenchymal stem cells into osteoblasts and chondrocytes.IHh plays an indispensable functional role in bone growth,development,and homeostasis and participates in the formation of intramembrane bone collars,proliferation,and maturation of chondrocytes.IHh is expressed in mature skull osteoblasts and can act as a promoter of bone factor regulation of Ptch and bone morphogenetic protein(BMP)expression to induce intramembrane ossification.Brain and muscle ARNT-like protein 1(BMAL1)can regulate the Hedgehog signaling pathway by binding to Ptch1 and Ihh,playing a crucial role in cartilage formation and endochondral osteogenesis in the temporomandibular joint.Hedgehog signal activators can improve the reduction in mandibular bone mass caused by BMAL1 deficiency.Hedgehog signaling imbalance can have a significant impact on bone development and lead to a series of bone diseases,such as abnormal bone development,fractures,osteoporosis,and osteoarthritis.The mechanism of the Hedgehog signaling pathway in relation to mandibular diseases has not been fully elucidated,and future research should seek to further explore Hedgehog signaling as a potential target for treating mandibular developmental-related diseases.