Xu Lingfeng, Zhang Yuejiao, Yang Hongxu, Liu Qian, Fan Peinan, Yu Jia, Zhang Mian, Yu Shibin, Wu Yaoping, Wang Meiqing
Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University, Xi'an, China.
Department of Oral Anatomy and Physiology and TMD, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
Osteoarthritis Cartilage. 2025 Apr;33(4):437-446. doi: 10.1016/j.joca.2024.11.011. Epub 2024 Dec 25.
Some cells in temporomandibular joint (TMJ) cartilage undergo proliferation in response to negative pressure, which can be induced in vivo by creating bilateral anterior elevation (BAE). TMJ cartilage harbours CD90-expressing cells, and CD90 expression increases under certain controlled conditions. The parathyroid hormone-related peptide (PTHrP) nuclear localisation segment (NLS) promotes chondrocyte proliferation, and mammalian target of rapamycin (mTOR) signalling plays a regulatory role in promoting PTHrP transcription. The purpose of this study was to determine the role of the mTOR/PTHrP-NLS axis in the proliferative responses of CD90 chondrocytes in TMJ cartilage to BAE.
CD90 cells were isolated from TMJ cartilage and subjected to negative pressure followed by RNA sequencing (RNA-seq). A PTHrP-NLS conditional mutation (CD90-CreER;Pthlh) mouse model was developed to obtain CD90 cell-specific PTHrP-NLS conditional mutation (Pthlh) littermate. CD90-Cre;Tsc1 mice and CD90-Cre;mTOR mice were generated to obtain Mtor conditional knockout (Mtor-CKO) and Tsc1-CKO littermates.
Using RNA-seq, the mTOR signalling pathway was identified as the most significant biological process occurring in superficial zone cells of the TMJ condylar cartilage under negative pressure. Proliferation of CD90 cells was stimulated in Tsc1-CKO littermates but inhibited in both Mtor-CKO and Pthlh littermates. BAE did not promote chondrocyte proliferation in either Mtor-CKO or Pthlh littermates. Administration of the PTHrP peptide to Mtor-CKO mice restored chondrocyte proliferation and rescued the promoting effect of BAE in TMJ cartilage.
CD90 chondrocytes in TMJ cartilage proliferate in response to negative pressure under the control of the TSC1-mTOR/PTHrP-NLS pathway.
颞下颌关节（TMJ）软骨中的一些细胞会对负压产生增殖反应，这种负压可通过制造双侧前上抬（BAE）在体内诱导产生。TMJ软骨中存在表达CD90的细胞，并且在某些可控条件下CD90表达会增加。甲状旁腺激素相关肽（PTHrP）核定位序列（NLS）可促进软骨细胞增殖，而雷帕霉素靶蛋白（mTOR）信号传导在促进PTHrP转录中起调节作用。本研究的目的是确定mTOR/PTHrP-NLS轴在TMJ软骨中CD90软骨细胞对BAE的增殖反应中的作用。
从TMJ软骨中分离出CD90细胞，对其施加负压后进行RNA测序（RNA-seq）。构建了PTHrP-NLS条件性突变（CD90-CreER;Pthlh）小鼠模型以获得CD90细胞特异性PTHrP-NLS条件性突变（Pthlh）同窝小鼠。生成了CD90-Cre;Tsc1小鼠和CD90-Cre;mTOR小鼠以获得Mtor条件性敲除（Mtor-CKO）和Tsc1-CKO同窝小鼠。
通过RNA-seq，mTOR信号通路被确定为在负压下TMJ髁突软骨表层细胞中发生的最显著生物学过程。Tsc1-CKO同窝小鼠中CD90细胞的增殖受到刺激，但在Mtor-CKO和Pthlh同窝小鼠中均受到抑制。BAE在Mtor-CKO或Pthlh同窝小鼠中均未促进软骨细胞增殖。给Mtor-CKO小鼠注射PTHrP肽可恢复软骨细胞增殖，并挽救BAE对TMJ软骨的促进作用。
TMJ软骨中的CD90软骨细胞在TSC1-mTOR/PTHrP-NLS途径的控制下对负压产生增殖反应。
