A dual role of HIF1α in regulating osteogenesis–angiogenesis coupling

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.

Mechanism of Liuwei Dihuang Pills in treating osteoporosis based on network pharmacology

“…[22] Additionally, HIF-1 is a crucial molecule that mediates bone-vascular interaction, and up-regulating the HIF-1 signaling pathway can promote angiogenesis and alleviate bone loss in ovariectomized (OVX) mice. [21,23] VEGF is a crucial regulator of angiogenesis that plays a significant role in bone metabolism. [24][25][26] Research has demonstrated that VEGF contributes to the differentiation of mesenchymal stem cells, making them more inclined towards osteogenic differentiation, by regulating the transcription factors RUNX2 and PPARγ2.…”

Hyperbaric oxygen therapy exerts anti‐osteoporotic effects in obese and lean D‐galactose‐induced aged rats

“…Both HIF‐1α and HIF‐2α are involved in managing prolonged oxidative damage in aging‐ and obesity‐related diseases 67–70 . Particularly, HIF‐1α plays a key role in the stimulation of osteoclast formation in aging‐ and obesity‐induced osteoporosis 70–72 . Consistently, HIF‐2α has been shown to play a role in the development of obesity and exerts anti‐osteogenic actions through upregulating the expression of receptor activator of nuclear factor kappa‐Β ligand (RANKL) that can influence osteoclastogenesis 69,73 .…”

“…[67][68][69][70] Particularly, HIF-1α plays a key role in the stimulation of osteoclast formation in agingand obesity-induced osteoporosis. [70][71][72] Consistently, HIF-2α has been shown to play a role in the development of obesity and exerts anti-osteogenic actions through upregulating the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) that can influence osteoclastogenesis. 69,73 Here, we discovered that HBOT also exerted the hyperoxia-hypoxic paradox in the bone of aging rats, regardless of obesity.…”

The Role of SIRT3 in the Osteoporosis

“…SIRT3 has been reported to be involved in a variety of aging-related diseases, such as Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, and bone diseases ( 20 , 21 ). A previous study showed that the senescence of bone mesenchymal stem cells (BMSCs) could lead to osteogenic damage and osteoporosis ( 22 ). And the maintenance of mitochondrial NAD + levels and the expression of SIRT3 could delay the senescence of MSCs ( 23 ).…”