1. Academic Validation
  2. Wnt/β-Catenin Promotes the Osteoblastic Potential of BMP9 Through Down-Regulating Cyp26b1 in Mesenchymal Stem Cells

Wnt/β-Catenin Promotes the Osteoblastic Potential of BMP9 Through Down-Regulating Cyp26b1 in Mesenchymal Stem Cells

  • Tissue Eng Regen Med. 2023 Apr 3. doi: 10.1007/s13770-023-00526-z.
Xin-Tong Yao # 1 2 Pei-Pei Li # 1 2 Jiang Liu 3 4 Yuan-Yuan Yang 1 2 Zhen-Ling Luo 5 Hai-Tao Jiang 6 Wen-Ge He 6 Hong-Hong Luo 1 2 Yi-Xuan Deng 1 2 Bai-Cheng He 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, No. 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
  • 2 Chongqing Key Laboratory for Biochemistry and Molecular Pharmacology, Chongqing, 400016, People's Republic of China.
  • 3 Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
  • 4 Department of Orthopedics, The 960th Hospital of the PLA Joint Logistics Support Force, Ji'nan, 250013, Shandong, People's Republic of China.
  • 5 Taizhou Food Inspection Centre, Taizhou, 318000, Zhejiang, People's Republic of China.
  • 6 Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People's Republic of China.
  • 7 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, No. 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China. bche@cqmu.edu.cn.
  • 8 Chongqing Key Laboratory for Biochemistry and Molecular Pharmacology, Chongqing, 400016, People's Republic of China. bche@cqmu.edu.cn.
  • # Contributed equally.
Abstract

Background: All-trans retinoic acid (ATRA) promotes the osteogenic differentiation induced by bone morphogenetic protein 9 (BMP9), but the intrinsic relationship between BMP9 and ATRA keeps unknown. Herein, we investigated the effect of Cyp26b1, a critical Enzyme of ATRA degradation, on the BMP9-induced osteogenic differentiation in mesenchymal stem cells (MSCs), and unveiled possible mechanism through which BMP9 regulates the expression of Cyp26b1.

Methods: ATRA content was detected with ELISA and HPLC-MS/MS. PCR, Western blot, and histochemical staining were used to assay the osteogenic markers. Fetal limbs culture, cranial defect repair model, and micro-computed tomographic were used to evaluate the quality of bone formation. IP and ChIP assay were used to explore possible mechanism.

Results: We found that the protein level of Cyp26b1 was increased with age, whereas the ATRA content decreased. The osteogenic markers induced by BMP9 were increased by inhibiting or silencing Cyp26b1 but reduced by exogenous Cyp26b1. The BMP9-induced bone formation was enhanced by inhibiting Cyp26b1. The cranial defect repair was promoted by BMP9, which was strengthened by silencing Cyp26b1 and reduced by exogenous Cyp26b1. Mechanically, Cyp26b1 was reduced by BMP9, which was enhanced by activating Wnt/β-catenin, and reduced by inhibiting this pathway. β-catenin interacts with Smad1/5/9, and both were recruited at the promoter of Cyp26b1.

Conclusions: Our findings suggested the BMP9-induced osteoblastic differentiation was mediated by activating retinoic acid signalling, viadown-regulating Cyp26b1. Meanwhile, Cyp26b1 may be a novel potential therapeutic target for the treatment of bone-related diseases or accelerating bone-tissue engineering.

Keywords

Bone regeneration; Cyp26b1; Mesenchymal stem cells; Osteogenic differentiation; Wnt/β-catenin signalling.

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