The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration.

Lihong Fan,Xiaoqian Dang,Jia Li,Kunzheng Wang,Zefeng Yu

doi:10.1155/2014/239356

Lihong Fan, Xiaoqian Dang + Show 3 more

Open Access

https://doi.org/10.1155/2014/239356

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Abstract

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-α via inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

Highlights

Hypoxia-inducible factors (HIFs) are DNA-binding transcription factors that transactivate a series of hypoxia-associated genes under hypoxic conditions to adapt to the decreased oxygen tension
HIFs are involved in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions
Genetic and pharmacological manipulations of HIFs have been proven to activate the HIF pathway in vitro and in vivo and to stimulate HIF-mediated pathways even under normoxic conditions (Table 1). This approach activates the beneficial aspects of the HIF system, and the HIF pathway has been a therapeutic target for the treatment of hypoxic-ischemic diseases

Summary

Introduction

Hypoxia-inducible factors (HIFs) are DNA-binding transcription factors that transactivate a series of hypoxia-associated genes under hypoxic conditions to adapt to the decreased oxygen tension. Considering the role of the HIF pathway in angiogenesis, erythrocytopoiesis, cell fate decisions, and cytoprotection, a large number of PHD inhibitors, especially the novel inhibitors of PHD, such as TM6008, TM6089, and FK506-binding protein 38 (FKBP38), have been found and used to activate the HIF pathway and acquire beneficial aspects of the HIF system [2, 3]. Increasing evidence suggests that the HIF pathway plays an essential role in bone regeneration and repair. The initial factor of bone regeneration is the upregulation of HIF-1α induced by hypoxia [4]. Resident cells, including chondrocytes and osteoblasts, sense the reduced oxygen tension via the PHDs and activate the HIFs, thereby increasing oxygen-regulated gene expression, including that of vascular endothelial growth factor (VEGF), to promote angiogenesis and osteogenesis. Therapeutic manipulation of the HIF pathway for bone fracture, osteoporosis, distraction osteogenesis, and bone tumour will be discussed

Hypoxia-Inducible Factors

Prolyl Hydroxylase Domain Proteins

Prolyl Hydroxylase Domain Protein Inhibitors

Role of the HIF Pathway in Angiogenic-Osteogenic Coupling

Applications of HIF Pathway in Bone Repair and Regeneration

Conclusion