Osteocytic HIF-1α Pathway Manipulates Bone Micro-structure and Remodeling via Regulating Osteocyte Terminal Differentiation.

Kaizhe Chen,Leilei Chang,Minglong Qiu,Peng Jia,Lianfang Zhang,Changwei Li,Jin Qi,Lianfu Deng,Kai Yang,Jian Zhao

doi:10.3389/fcell.2021.721561

Abstract

The activation of hypoxia-inducible factor 1α (HIF-1α) signaling has promising implications for the treatment of bone diseases such as osteoporosis and skeletal fractures. However, the effects of manipulating HIF-1α pathway on bone micro-structure and remodeling should be fully studied before the clinical application of therapeutics that interfere with the HIF-1α pathway. In this study, we found that osteocyte-specific HIF-1α pathway had critical role in manipulating bone mass accrual, bone material properties and micro-structures, including bone mineralization, bone collagen fiber formation, osteocyte/canalicular network, and bone remodeling. In addition, our results suggest that osteocyte-specific HIF-1α pathway regulates bone micro-structure and remodeling via impairing osteocyte differentiation and maturation.

Highlights

Hypoxia-inducible factor (HIF) α is a major transcriptional regulator of adaptive responses to low oxygen levels (Zuo et al, 2015)
The impaired osteocyte maturation caused by CA- hypoxia-inducible factor 1α (HIF-1α) in mineralizing osteocyte facilitated osteogenesis in mesenchymal stem cells (MSCs) and impaired osteoclastic differentiation of bone marrow monocytes (BMMs), which resulted in disrupted bone remodeling and may be responsible for the abnormal bone formation observed in osteocyte-specific Vhl deficient mice
We examined the effects of CA-HIF-1α on osteoclastic differentiation using a three-dimensional (3D) system, in which BMMs were cocultured with IDG-SW3 cells with or without Vhl-small interfering RNA (siRNA) transfection (Figure 6F); tartrate-resistant acid phosphatase (TRAP) staining showed that osteoclastic differentiation was dampened in BMMs cultured with Vhl-siRNA-transfected IDG-SW3 cells compared to the control (Figure 6G)

Summary

INTRODUCTION

Hypoxia-inducible factor (HIF) α is a major transcriptional regulator of adaptive responses to low oxygen levels (Zuo et al, 2015). The deletion of PHD or VHL stabilizes HIF-1α, which causes an increase in bone mass by regulating the bone formation activity of osteoblasts and the bone resorption activity of osteoclasts (Zhang et al, 2014; Wu et al, 2015; Kang et al, 2017; Loots et al, 2018). Activation of the osteocytic HIF-1α pathway via VHL deletion causes an excessive bone mass phenotype (Loots et al, 2018). We deleted Vhl in mouse mineralizing osteocytes to generate mice in which the HIF-1α pathway was constitutively activated, which resulted in excessive immature bone accumulation with impaired bone material properties and micro-structures, including abnormal mineralization, disrupted collagen fiber formation, and an impaired osteocyte/canalicular network, which may result from impaired osteocyte terminal differentiation. The impaired osteocyte maturation caused by CA- HIF-1α in mineralizing osteocyte facilitated osteogenesis in mesenchymal stem cells (MSCs) and impaired osteoclastic differentiation of bone marrow monocytes (BMMs), which resulted in disrupted bone remodeling and may be responsible for the abnormal bone formation observed in osteocyte-specific Vhl deficient mice

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT