TCF12 regulates the TGF-β/Smad2/3 signaling pathway to accelerate the progression of osteoarthritis by targeting CXCR4

Hui Zheng; Jianli Fang; Wei Lu; Youhui Liu; Sixu Chen; Guangxin Huang; Yuming Zou; Shu Hu; Yongxu Zheng; Hang Fang; Rongkai Zhang

doi:10.1016/j.jot.2023.11.006

TCF12 regulates the TGF-β/Smad2/3 signaling pathway to accelerate the progression of osteoarthritis by targeting CXCR4

J Orthop Translat. 2023 Dec 27:44:35-46. doi: 10.1016/j.jot.2023.11.006. eCollection 2024 Jan.

Authors

Hui Zheng^{1

2

3}, Jianli Fang^{1

2

3}, Wei Lu^{1

2

3}, Youhui Liu^{1

2

3}, Sixu Chen^{1

2

3}, Guangxin Huang^{1

2

3}, Yuming Zou^{1

2

3}, Shu Hu^{1

2

3}, Yongxu Zheng^{1

4

2

5}, Hang Fang^{1

2

3}, Rongkai Zhang^{1

4

2

3

6

5}

Affiliations

¹ Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics, Guangdong Province), Guangzhou, Guangdong, China.
² Orthopedic Hospital of Guangdong Province, Guangzhou, Guangdong, China.
³ Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, Guangdong, China.
⁴ Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, China.
⁵ The Air Force Hospital of Southern Theater Command, Guangzhou, Guangdong, China.
⁶ Linzhi People's Hospital, Tibet Autonomous Region, China.

Abstract

Objective: 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.

Methods: 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.

Result: 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).

Conclusion: 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.

The translational potential of this article: 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.

Keywords: Aging; CXCR4; Osteoarthritis; TCF12; TGF-β.