Zheng Hui, Fang Jianli, Lu Wei, Liu Youhui, Chen Sixu, Huang Guangxin, Zou Yuming, Hu Shu, Zheng Yongxu, Fang Hang, Zhang Rongkai
Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics, Guangdong Province), Guangzhou, Guangdong, China.
Orthopedic Hospital of Guangdong Province, Guangzhou, Guangdong, China.
J Orthop Translat. 2023 Dec 27;44:35-46. doi: 10.1016/j.jot.2023.11.006. eCollection 2024 Jan.
Osteoarthritis (OA), which involves total joint damage and dysfunction, is a leading cause of disability worldwide. However, its exact pathogenesis remains unclear. Here, we identified TCF12 as an important regulator of the progression of OA.
qRT-PCR, immunoblotting and immunohistochemistry (IHC) were used to detect the expression level of TCF12. The interaction of TCF12 with its downstream factor CXCR4 was assessed by Western blotting, immunofluorescence, qRT-PCR and luciferase assays. A mouse model was generated to examine the functions and mechanism of TCF12 in vivo.
TCF12 expression was upregulated in chondrocytes stimulated with IL-1β and osteoarthritic chondrocytes. TCF12 upregulates the expression of CXCR4 and leads to dysfunction of the TGF-β signaling pathway. Furthermore, knockdown of TCF12 alleviated cartilage damage in a mouse model generated by destabilization of the medial meniscus (DMM).
TCF12 aggravates the progression of OA by targeting CXCR4 and then activating the TGF-β signaling pathway, suggesting that TCF12 may be a new target for the treatment of OA.
Transcription Factor 12(TCF12), is known to regulate cell development and differentiation, It has been widely studied in various organs and diseases, but its role in OA remains unclear. Here, we identified Transcription Factor 12(TCF12) as an important regulator mediating chondrocyte senescence and cartilage extracellular matrix degradation indicating its role in OA. We found that TCF12 expression was upregulated both locally and systemically as OA advanced in patients with OA, and in mice after DMM surgery to induce OA. TCF12 expression caused striking progressive articular cartilage damage, synovial hyperplasia in OA mice, and remarkably, it was relieved by intra-articular administration of mutant mouse TCF12 lentiviral vector (shTCF12). Furthermore, TCF12 upregulated the expression of CXCR4, leading to exacerbation of experimental OA partially through activation of TGF-β signaling in chondrocytes. TCF12 expression was upregulated in chondrocytes treated with IL-1β and osteoarthritic chondrocytes. Our findings established an essential role of TCF12 in chondrocyte senescence and cartilage extracellular matrix degradation during OA, and identified intra-articular injection of TCF12 as a potential therapeutic strategy for OA prevention and treatment.
骨关节炎（OA）涉及全关节损伤和功能障碍，是全球范围内导致残疾的主要原因。然而，其确切发病机制仍不清楚。在此，我们确定TCF12是OA进展的重要调节因子。
采用qRT-PCR、免疫印迹和免疫组织化学（IHC）检测TCF12的表达水平。通过蛋白质印迹、免疫荧光、qRT-PCR和荧光素酶测定评估TCF12与其下游因子CXCR4的相互作用。构建小鼠模型以研究TCF12在体内的功能和机制。
在IL-1β刺激的软骨细胞和骨关节炎软骨细胞中，TCF12表达上调。TCF12上调CXCR4的表达并导致TGF-β信号通路功能障碍。此外，在通过内侧半月板不稳定（DMM）构建的小鼠模型中，敲低TCF12可减轻软骨损伤。
TCF12通过靶向CXCR4进而激活TGF-β信号通路加重OA进展，提示TCF12可能是OA治疗的新靶点。
已知转录因子12（TCF12）调节细胞发育和分化，它已在各种器官和疾病中得到广泛研究，但其在OA中的作用仍不清楚。在此，我们确定转录因子12（TCF12）是介导软骨细胞衰老和软骨细胞外基质降解的重要调节因子，表明其在OA中的作用。我们发现，随着OA在OA患者中进展以及在DMM手术诱导OA后的小鼠中，TCF12表达在局部和全身均上调。TCF12表达导致OA小鼠出现明显的进行性关节软骨损伤、滑膜增生，并且显著地，通过关节内注射突变型小鼠TCF12慢病毒载体（shTCF12）可使其得到缓解。此外，TCF12上调CXCR4的表达，部分通过激活软骨细胞中的TGF-β信号通路导致实验性OA加重。在用IL-1β处理的软骨细胞和骨关节炎软骨细胞中，TCF12表达上调。我们的研究结果确立了TCF12在OA期间软骨细胞衰老和软骨细胞外基质降解中的重要作用，并确定关节内注射TCF12是OA预防和治疗的潜在策略。
