HIF1A overexpression promotes osteoblast differentiation through activation of autophagy to alleviate osteoporosis

Aug 19, 2025Scientific reports

Higher HIF1A levels help bone-building cells develop by activating cell recycling, which may reduce osteoporosis

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Abstract

Overexpression of HIF-1α significantly increases bone mineral density and trabecular thickness in osteoporotic rat models.

HIF-1α overexpression promotes osteoblast proliferation and enhances markers of osteogenic differentiation, such as alkaline phosphatase staining and calcium nodule formation.
Increased protein levels of osteocalcin, osteoprotegerin, and several -related proteins were observed with HIF-1α overexpression.
HIF-1α may facilitate osteoblast differentiation by promoting autophagy, as indicated by the elevated expression of autophagy-related proteins.
In vivo results showed improved bone morphology and increased bone mineral density in femurs of rats with HIF-1α overexpression.
The study found decreased trabecular separation and structural model index, suggesting enhanced bone structure following HIF-1α overexpression.

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Objective (OP) is a systemic skeletal disease that increases the risk of fractures by weaking bone. Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in osteogenesis and osteoblastic differentiation. The purpose of this study is to examine the underlying mechanism of HIF-1α overexpression and its impact on osteoblast development. Methods First, we used the inhibitor 3-MA in conjunction with either a control lentivirus or an HIF-1α overexpression lentivirus to transfect rat osteoblasts in osteogenic induction media for 3, 7, 14, and 21 days. The effects of HIF-1α overexpression on osteogenic differentiation were evaluated using CCK-8, alkaline phosphatase (ALP) staining, and Alizarin Red staining. Furthermore, we investigated the mechanism by which HIF-1α overexpression mediates autophagy to regulate osteogenic differentiation through immunofluorescence, western blot, and transmission electron microscopy. Ovariectomy (OVX) was performed to establish an osteoporotic rat model. The impact of HIF-1α overexpression on autophagy and bone metabolism was evaluated by locally injecting HIF-1α overexpression lentivirus or control lentivirus, in combination with HE staining, micro-CT, immunohistochemistry, ELISA, western blot, and transmission electron microscopy. Results Overexpression of HIF-1a promotes osteoblast proliferation and enhances ALP staining as well as calcium nodule formation. In addition, the overexpression of HIF-1a significantly increases the relative protein expression levels of osteocalcin (OCN), osteoprotegerin (OPG), HIF-1a, BNIP3, Beclin1, ATG5, and LC3 II/I. This indicates that HIF-1a may facilitate osteoblast differentiation by promoting autophagy. These findings were further corroborated by in vivo experiments, which demonstrated improved pathological morphology in rat femurs, alongside increased bone mineral density (BMD), trabecular thickness (Tb. Th), bone volume/total volume ratio (BV/TV), and trabecular number (Tb. N). Additionally, there was a decrease in trabecular separation (Tb. Sp) and structural model index (SMI), along with upregulated expression of OCN, OPG, HIF-1α, BNIP3, Beclin1, ATG5, and LC3 II. Conclusion HIF-1a overexpression can promote osteogenic differentiation and ameliorate osteoporosis through the induction of autophagy. These insights provide a valuable reference for its potential application in targeted therapy.

Key numbers

0.0001

Increase in Osteoblast Proliferation

Compared to negative control group (ov-NC).

0.0008

Bone Mineral Density (BMD) Increase

Compared to model group.

0.0005

Decrease in Trabecular Separation (Tb.Sp)

Compared to model group.

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HIF1A overexpression promotes osteoblast differentiation through activation of autophagy to alleviate osteoporosis

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