2. Academic Validation
  3. Long noncoding RNA XIST modulates microRNA-135/CREB1 axis to influence osteogenic differentiation of osteoblast-like cells in mice with tibial fracture healing

Long noncoding RNA XIST modulates microRNA-135/CREB1 axis to influence osteogenic differentiation of osteoblast-like cells in mice with tibial fracture healing

  • Hum Cell. 2022 Jan;35(1):133-149. doi: 10.1007/s13577-021-00629-6.
Ying Zhang  # 1 2,  Qiang Yuan  # 1 3,  Qiushi Wei 4,  Peifeng Li 1,  Zhikun Zhuang 5,  Jitian Li 1,  Youwen Liu 1,  Leilei Zhang 1,  Zhinan Hong 4,  Wei He 4,  Haibin Wang 6,  Wuyin Li 7
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), No.82, Qiming South Road, Fuhe District, Luoyang, 471002, Henan, People's Republic of China.
  • 2 Postdoctoral Mobile Station, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
  • 3 Luoyang Graduate Training Department, Henan University of Traditional Chinese Medicine, Zhengzhou, 450046, Henan, People's Republic of China.
  • 4 Department of Orthopaedics, Institute of Orthopaedics of Guangzhou University of Chinese Medicine (The Third Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine), Guangzhou, 510240, Guangdong, People's Republic of China.
  • 5 First Clinical Medical College, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China.
  • 6 Department of Orthopaedics Laboratory, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510405, Guangdong, People's Republic of China. DrWhaibin@163.com.
  • 7 Department of Orthopaedics, Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), No.82, Qiming South Road, Fuhe District, Luoyang, 471002, Henan, People's Republic of China. Wuyinli11061@163.com.
  • # Contributed equally.
PMID: 34635983 DOI: 10.1007/s13577-021-00629-6
Abstract

Fracture healing is a complex event with the involvement of many cell systems, cytokines, as well as mRNAs. Herein, we report the interactions among long noncoding RNA X-inactive specific transcript (XIST)/microRNA-135 (miR-135)/cAMP response element-binding protein 1 (CREB1) axis during fracture healing. We observed increased expression of XIST in patients with long-term unhealed fracture by microarray analysis. Subsequently, a mouse model with tibial fracture and a cell model using osteoblast-like MC3T3-E1 cells were generated. The XIST overexpression during fracture healing decreased proliferation and differentiation of MC3T3-E1 cells, while silencing of XIST facilitated MC3T3-E1 cell growth. Furthermore, miR-135 targeted CREB1 and negatively regulated its expression. XIST acted as a Sponge for miR-135, thereby upregulating CREB1 and promoting the activity of the TNF-α/RANKL pathway. Transfection of miR-135 inhibitor or CREB1 overexpression blocked the stimulating effects of XIST knockdown on MC3T3-E1 cell growth. Besides, specific inhibitors of the TNF-α/RANKL pathway reversed the repressive role of XIST in cell osteogenic differentiation. All in all, these findings suggest that XIST knockdown induces the differentiation of osteoblast-like cells via regulation of the miR-135/CREB1/TNF-α/RANKL axis. XIST, as a consequence, represents an attractive therapeutic strategy to accelerate fracture healing.

Keywords

CREB1; Fracture healing; Long noncoding RNA XIST; Osteoblast-like cells; TNF-α/RANKL pathway; microRNA-135.

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