2. Academic Validation
  3. A dual role of HIF1α in regulating osteogenesis-angiogenesis coupling

A dual role of HIF1α in regulating osteogenesis-angiogenesis coupling

  • Stem Cell Res Ther. 2022 Feb 5;13(1):59. doi: 10.1186/s13287-022-02742-1.
Jingjing Shao 1 2,  Shibo Liu 1 3,  Min Zhang 1 2,  Shujiang Chen 1 2,  Shuaiqi Gan 1 2,  Chenfeng Chen 1 2,  Wenchuan Chen 1 2,  Lei Li 4 5,  Zhimin Zhu 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No 14, Sec. 3, Renminnan Road, Chengdu, 610041, People's Republic of China.
  • 2 Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
  • 3 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
  • 4 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No 14, Sec. 3, Renminnan Road, Chengdu, 610041, People's Republic of China. [email protected].
  • 5 Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 6 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No 14, Sec. 3, Renminnan Road, Chengdu, 610041, People's Republic of China. [email protected].
  • 7 Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China. [email protected].
PMID: 35123567 DOI: 10.1186/s13287-022-02742-1
Abstract

Objectives: The hypoxia-inducible factor 1-α (HIF1α), a key molecule in mediating bone-vessel crosstalk, has been considered a promising target for treating osteoporosis caused by gonadal Hormones. However, senile osteoporosis, with accumulated senescent cells in aged bone, has a distinct pathogenesis. The study aimed at revealing the unknown role of HIF1α in aged bone, thus broadening its practical application in senile osteoporosis.

Materials and methods: Femurs and tibias were collected from untreated mice of various ages (2 months old, 10 months old, 18 months old) and treated mice (2 months old, 18 months old) underwent 4-w gavage of 2-methoxyestradiol (a kind of HIF1α inhibitor). Bone-vessel phenotypes were observed by microfil infusion, micro-CT and HE staining. Markers of senescence, osteogenesis, angiogenesis, oxidative stress and expression of HIF1α were detected by senescence β-galactosidase staining, qRT-PCR, western blot and immunostaining, respectively. Furthermore, bone mesenchymal stem cells from young mice (YBMSCs) and aged mice (ABMSCs) were transfected by knockout siRNA and overexpression plasmid of HIF1α. Senescence β-galactosidase staining, Cell Counting Kit-8, transwell assay, Alkaline Phosphatase staining, alizarin red-S staining and angiogenesis tests were utilized to assess the biological properties of two cell types. Then, Pifithrin-α and Nutlin-3a were adopted to intervene p53 of the two cells. Finally, H2O2 on YBMSCs and NAC on ABMSCs were exploited to change their status of oxidative stress to do a deeper detection.

Results: Senescent phenotypes, impaired osteogenesis-angiogenesis coupling and increased HIF1α were observed in aged bone and ABMSCs. However, 2-methoxyestradiol improved bone-vessel metabolism of aged mice while damaged that of young mice. Mechanically, HIF1α showed opposed effects in regulating the cell migration and osteogenesis-angiogenesis coupling of YBMSCs and ABMSCs, but no remarked effect on the proliferation of either cell type. Pifithrin-α upregulated the osteogenic and angiogenic markers of HIF1α-siRNA-transfected YBMSCs, and Nutlin-3a alleviated those of HIF1α-siRNA-transfected ABMSCs. The HIF1α-p53 relationship was negative in YBMSCs and NAC-treated ABMSCs, but positive in ABMSCs and H2O2-treated YBMSCs.

Conclusion: The dual role of HIF1α in osteogenesis-angiogenesis coupling may depend on the ROS-mediated HIF1α-p53 relationship. New awareness about HIF1α will be conducive to its future application in senile osteoporosis.

Keywords

HIF1α; Osteogenesis–angiogenesis coupling; ROS; Senile osteoporosis; p53.

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