HIF/Ca2+/NO/ROS is critical in roxadustat treating bone fracture by stimulating the proliferation and migration of BMSCs

Chen, Chunxia; Yan, Shihai; Qiu, Shuang; Geng, Zhirong; Wang, Zhilin

doi:10.1016/j.lfs.2020.118684

Cited by 22 publications

(14 citation statements)

References 43 publications

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“…LLLT has gradually been widely adopted clinically. In recent years, LLLT has also been used for wound healing, fracture healing, repair of calvaria bone defects, and dental tissue regeneration due to its potential to promote tissue regeneration [ 22 , 38 , 40 , 41 ]. Although the biological mechanisms underlying the effects are not fully understood, it is generally believed that the regenerative potential of LLLT may be related to its promotion of cell proliferation, angiogenesis, and differentiation of stem cells, among other effects [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence has indicated that cells exposed to laser irradiation undergo a sustained increase in the production of endogenous reactive oxygen species (ROS) through changing mitochondrial membrane potential. ROS can promote the oxidation of ferrous ions (Fe2 +) and inhibit the activation of proline hydroxylases (PHDs), thereby inhibition of HIF-1α degradation [ 22 , 23 ]. Thus, the ROS/HIF-1α signal pathway plays a critical role in the osteogenic progression induced by LLLT treatment.…”

Section: Introductionmentioning

confidence: 99%

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Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis

Bai

Kou

et al. 2021

Stem Cell Res Ther

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Background Bone tissue engineering is a new concept bringing hope for the repair of large bone defects, which remains a major clinical challenge. The formation of vascularized bone is key for bone tissue engineering. Growth of specialized blood vessels termed type H is associated with bone formation. In vivo and in vitro studies have shown that low level laser therapy (LLLT) promotes angiogenesis, fracture healing, and osteogenic differentiation of stem cells by increasing reactive oxygen species (ROS). However, whether LLLT can couple angiogenesis and osteogenesis, and the underlying mechanisms during bone formation, remains largely unknown. Methods Mouse bone marrow mesenchymal stem cells (BMSCs) combined with biphasic calcium phosphate (BCP) grafts were implanted into C57BL/6 mice to evaluate the effects of LLLT on the specialized vessel subtypes and bone regeneration in vivo. Furthermore, human BMSCs and human umbilical vein endothelial cells (HUVECs) were co-cultured in vitro. The effects of LLLT on cell proliferation, angiogenesis, and osteogenesis were assessed. Results LLLT promoted the formation of blood vessels, collagen fibers, and bone tissue and also increased CD31hiEMCNhi-expressing type H vessels in mBMSC/BCP grafts implanted in mice. LLLT significantly increased both osteogenesis and angiogenesis, as well as related gene expression (HIF-1α, VEGF, TGF-β) of grafts in vivo and of co-cultured BMSCs/HUVECs in vitro. An increase or decrease of ROS induced by H2O2 or Vitamin C, respectively, resulted in an increase or decrease of HIF-1α, and a subsequent increase and decrease of VEGF and TGF-β in the co-culture system. The ROS accumulation induced by LLLT in the co-culture system was significantly decreased when HIF-1α was inhibited with DMBPA and was followed by decreased expression of VEGF and TGF-β. Conclusions LLLT enhanced vascularized bone regeneration by coupling angiogenesis and osteogenesis. ROS/HIF-1α was necessary for these effects of LLLT. LLLT triggered a ROS-dependent increase of HIF-1α, VEGF, and TGF-β and resulted in subsequent formation of type H vessels and osteogenic differentiation of mesenchymal stem cells. As ROS also was a target of HIF-1α, there may be a positive feedback loop between ROS and HIF-1α, which further amplified HIF-1α induction via the LLLT-mediated ROS increase. This study provided new insight into the effects of LLLT on vascularization and bone regeneration in bone tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis

Bai

Kou

et al. 2021

Stem Cell Res Ther

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“…Clinically, a number of orally administered, small molecule HIF prolyl hydroxylase inhibitors are in trials for treatment of anemia. Roxadustat, for example, is approved for use in China and the European Union as a treatment for renal induced chronic anemia [23] . As with anti-sclerostin antibody treatment, ample preclinical evidence in animal models would suggest that prolyl-hydroxylase inhibitors might have positive effects on human fracture treatment [24] .…”

Section: Approachesmentioning

confidence: 99%

“…Roxadustat, for example, is approved for use in China and the European Union as a treatment for renal induced chronic anemia. [ 23 ] As with anti-sclerostin antibody treatment, ample preclinical evidence in animal models would suggest that prolyl-hydroxylase inhibitors might have positive effects on human fracture treatment. [ 24 ] Currently, Roxadustat has not been approved by the FDA for treatment of anemia in chronic kidney disease due to concerns over its safety profile.…”

Section: Approachesmentioning

confidence: 99%

Enhancing fracture repair: cell-based approaches

Wixted

Challa

Nazarian

2022

OTA International: The Open Access Journal of Orthopaedic Trauma

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Fracture repair is based both on the macrolevel modulation of fracture fragments and the subsequent cellular activity. Surgeons have also long recognized other influences on cellular behavior: the effect of the fracture or subsequent surgery on the available pool of cells present locally in the periosteum, the interrelated effects of fragment displacement, and construct stiffness on healing potential, patient pathophysiology and systemic disease conditions (such as diabetes), and external regulators of the skeletal repair (such as smoking or effect of medications). A wide variety of approaches have been applied to enhancing fracture repair by manipulation of cellular biology. Many of these approaches reflect our growing understanding of the cellular physiology that underlies skeletal regeneration. This review focuses on approaches to manipulating cell lineages, influencing paracrine and autocrine cell signaling, or applying other strategies to influence cell surface receptors and subsequent behavior. Scientists continue to evolve new approaches to pharmacologically enhancing the fracture repair process.

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“…Roxadustat, a novel small molecule HIF-PHD inhibitor that can stabilize HIF-α expression, is currently in clinical use for the treatment of renal anemia [ 13 , 14 ]. As a potent HIF-α stabilizer, roxadustat was found to promote fracture healing by stimulating the proliferation and migration of bone marrow mesenchymal stem cells, in which activation of the HIF-1α pathway was shown to be critical [ 15 ]. Moreover, roxadustat inhibited osteoclast differentiation and reduced bone resorption in vitro [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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

Zhu

et al. 2022

J Orthop Surg Res

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Background Osteoporosis is a very common skeletal disorder that increases the risk of fractures. However, the treatment of osteoporosis is challenging. Hypoxia-inducible factor-1α (HIF-1α) 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-1α and Wnt/β-catenin pathways were evaluated. Furthermore, osteoblast differentiation was assessed again after HIF-1α expression knockdown or inhibition of the Wnt/β-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-1α and β-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-1α and Wnt/β-catenin pathways. HIF-1α knockdown or Wnt/β-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-1α and β-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.

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HIF/Ca2+/NO/ROS is critical in roxadustat treating bone fracture by stimulating the proliferation and migration of BMSCs

Cited by 22 publications

References 43 publications

Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis

Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis

Enhancing fracture repair: cell-based approaches

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

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