Research Alert
BACKGROUND
Newswise — Osteoporosis (OP) has become a major public health problem worldwide. Most OP treatments are based on the inhibition of bone resorption, and it is necessary to identify additional treatments aimed at enhancing osteogenesis. In the bone marrow (BM) niche, bone mesenchymal stem cells (BMSCs) are exposed to a hypoxic environment. Recently, a few studies have demonstrated that hypoxia-inducible factor 2alpha (HIF-2α) is involved in BMSC osteogenic differentiation, but the molecular mechanism involved has not been determined.
AIM
To investigate the effect of HIF-2α on the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells (HSCs) in the BM niche on the progression of OP.
METHODS
Mice with BMSC-specific HIF-2α knockout (Prx1-Cre;Hif-2αfl/fl mice) were used for in vivo experiments. Bone quantification was performed on mice of two genotypes with three interventions: Bilateral ovariectomy, semilethal irradiation, and dexamethasone treatment. Moreover, the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes. In vitro, the HIF-2α agonist roxadustat and the HIF-2α inhibitor PT2399 were used to investigate the function of HIF-2α in BMSC osteogenic and adipogenic differentiation. Finally, we investigated the effect of HIF-2α on BMSCs via treatment with the mechanistic target of rapamycin (mTOR) agonist MHY1485 and the mTOR inhibitor rapamycin.
RESULTS
The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions. In vitro, Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2α agonist roxadustat, and after 7 d of BMSC adipogenic differentiation, the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased; in addition, after 14 d of osteogenic differentiation, BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes. The opposite effects were shown for mouse BMSCs treated with the HIF-2α inhibitor PT2399. The mTOR inhibitor rapamycin was used to confirm that HIF-2α regulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway. Consequently, there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice.
CONCLUSION
Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.
Key Words: Hypoxia-inducible factor-2α, Bone marrow niche, Bone mesenchymal stem cells, Osteoporosis, Osteogenic/adipogenic differentiation, Mechanistic target of rapamycin signaling pathway
Core Tip: This manuscript explores the role of hypoxia-inducible factor 2alpha (HIF-2α) in bone mesenchymal stem cell (BMSC) osteogenic differentiation in the bone marrow niche, a role that is still unclear and controversial, via in vivo and in vitro experiments. We verified that downregulation of HIF-2α inhibits osteogenesis in vivo by generating mice with BMSC-specific HIF-2α knockout and applying interventions such as bilateral ovariectomy, semilethal irradiation, and treatment with dexamethasone. In vitro, we found that downregulation of HIF-2α can inhibit osteogenesis and increase adipogenesis by suppressing the mechanistic target of rapamycin signaling pathway, which may lead to the identification of drug target genes for the clinical treatment of osteoporosis.
- Citation: Wang LL, Lu ZJ, Luo SK, Li Y, Yang Z, Lu HY. Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health. World J Stem Cells 2024; 16(4): 389-409
- URL: https://www.wjgnet.com/1948-0210/full/v16/i4/389.htm
- DOI: https://dx.doi.org/10.4252/wjsc.v16.i4.389
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