Roxadustat promotes osteoblast differentiation and prevents estrogen deficiency-induced bone loss by stabilizing HIF-1α and activating the Wnt/β-catenin signaling pathway

Background: Osteoporosis is a very common skeletal disorder that increases the risk of fractures. However, the treatment of osteoporosis is challenging. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in bone metabolism. Roxadustat is a novel HIF stabilizer, and its effects on bone metabolism remain unknown. This study aimed to investigate the effects of roxadustat on osteoblast differentiation and bone remodeling in an ovariectomized (OVX) rat model. Methods: In vitro, primary mouse calvarial osteoblasts were treated with roxadustat. Alkaline phosphatase (ALP) activity and extracellular matrix mineralization were assessed. The mRNA and protein expression levels of osteogenic markers were detected. The effects of roxadustat on the HIF-1 alpha and Wnt/beta-catenin pathways were evaluated. Furthermore, osteoblast differentiation was assessed again after HIF-1 alpha expression knockdown or inhibition of the Wnt/beta-catenin pathway. In vivo, roxadustat was administered orally to OVX rats for 12 weeks. Then, bone histomorphometric analysis was performed. The protein expression levels of the osteogenic markers HIF-1 alpha and beta-catenin in bone tissue were detected. Results:In vitro, roxadustat significantly increased ALP staining intensity, enhanced matrix mineralization and upregulated the expression of osteogenic markers at the mRNA and protein levels in osteoblasts compared with the control group. Roxadustat activated the HIF-1 alpha and Wnt/beta-catenin pathways. HIF-1 alpha knockdown or Wnt/beta-catenin pathway inhibition significantly attenuated roxadustat-promoted osteoblast differentiation. In vivo, roxadustat administration improved bone microarchitecture deterioration and alleviated bone loss in OVX rats by promoting bone formation and inhibiting bone resorption. Roxadustat upregulated the protein expression levels of the osteogenic markers, HIF-1 alpha and beta-catenin in the bone tissue of OVX rats. Conclusion:Roxadustat promoted osteoblast differentiation and prevented bone loss in OVX rats. The use of roxadustat may be a new promising strategy to treat osteoporosis.

Automated summary

This study investigated the effects of roxadustat on osteoblast differentiation and bone remodeling in an OVX rat model. The results showed that roxadustat promoted osteoblast differentiation, prevented bone loss, and improved bone microarchitecture in OVX rats. Therefore, roxadustat may be a promising strategy for the treatment of osteoporosis.