FGF9/Msx2信号轴在创伤性颞下颌关节周围异位骨化中的作用及其机制研究

Traumatic heterotopic ossification around temporomandibular joint (THO-TMJ) can lead to restriction of mouth opening, as well as craniofacial deformities, but the pathogenesis of this disease is still unclear. Based on our THO-TMJ mouse model, our previous findings showed that injured condylar cartilage greatly contributed to the pathogenesis of THO-TMJ, and the expression of fibroblast growth factor 9 (FGF9) and the homeobox gene Msx2 were significantly up-regulated in the heterotopic ossification region. Both Msx2 and FGF9 play crucial roles in cranial neural crest cells differentiation, bone development and the formation of heterotopic bone around joint, and FGF9 could regulate the expression of Msx2. These findings implied that FGF9/Msx2 signaling axis might exhibit regulatory effect on the pathogenesis of THO-TMJ. In this study, we try to explore the effect and mechanism of FGF9/Msx2 signaling axis during the development of THO-TMJ based on the existing mouse models and molecular biology techniques. It is expected to illuminate the origin of pre-osteogenic cells, and the signaling pathway that trigger the development of THO-TMJ. Meanwhile, it is also expected to clarify the effect and mechanism of FGF9/Msx2 signaling pathway during the development of THO-TMJ. In addition, suitable small molecular drug and stem cell intervention protocols are expected to be established. Accordingly, useful clues for the prevention, diagnosis and treatment of THO-TMJ would be offered.

创伤性颞下颌关节周围异位骨化（THO-TMJ）常可致张口受限和牙颌面畸形，其发病机制尚不完全明确。课题组前期构建了THO-TMJ小鼠模型，发现受伤的髁突软骨对于异位骨化的发生尤为关键，且成纤维生长因子9（FGF9）和同源盒基因Msx2在异位骨化区域呈显著高表达。FGF9与Msx2均对颅神经嵴细胞分化、骨发育及关节区异位骨形成十分重要，FGF9可同时调控Msx2的表达，提示FGF9/Msx2信号轴与THO-TMJ的发生密切相关。本课题拟基于模式动物及体内外分子生物学实验，旨在明确THO-TMJ发生过程中成骨前体细胞的来源及创伤启动异位骨化的信号途径，阐明FGF9/Msx2信号轴在上述过程中的作用及机制，并探索THO-TMJ的小分子药物及干细胞干预的可行性方案，为该疾病的防治提供新的思路。

创伤性颞下颌关节周围异位骨化可致张口受限及牙颌面畸形，危害极大，但发病机制、防治手段尚不完全明确。项目组构建小鼠创伤性颞下颌关节周围异位骨化模型，证明受损髁突软骨及其分泌的TGF-β2、IGF-1在创伤性颞下颌关节周围异位骨化的发生中发挥关键作用；构建Tie2-Cre::Loxp-STOP-Loxp-lacz及CKMM-Cre::Loxp-STOP-Loxp-lacz双转基因示踪小鼠，证明内皮细胞及肌肉间充质细胞可作为成骨/成软骨前体来源细胞，促进创伤性颞下颌关节周围异位骨化的进展；阐述炎症微环境启动了创伤性颞下颌关节周围异位骨化，应用体内模型证实选择性COX-2抑制剂塞来昔布可抑制创伤性颞下颌关节周围异位骨化的发生，提示Bmpr1b为其中的关键因子；应用体外模型证实塞来昔布可抑制炎症环境下ATDC-5细胞系的成软骨向分化作用，为该疾病的防治提供了新思路。同时，TGF-β2及IGF-1介导颞下颌关节周围异位骨化发生的分子生物学机制、其与Msx2/FGF9信号轴的关系及塞来昔布调控Bmpr1b防治颞下颌关节周围异位骨化的机理仍有待后续深入研究。