Persistent Low Level of Osterix Accelerates Interleukin-6 Production and Impairs Regeneration after Tissue Injury

Wook-Young Baek,Min-A Lee,Kwon-Moo Park,Tae-Hwan Kwon,Yeo Hyang Kim,Benoit De Crombrugghe,Seung-Yoon Park,Jung-Eun Kim,Sophie Mouillet-Richard

doi:10.1371/journal.pone.0069859

Abstract

Osterix (Osx) is an essential transcription factor for osteoblast differentiation and bone formation. Osx knockout show a complete absence of bone formation, whereas Osx conditional knockout in osteoblasts produce an osteopenic phenotype after birth. Here, we questioned whether Osx has a potential role in regulating physiological homeostasis. In Osx heterozygotes expressing low levels of Osx in bones, the expression levels of pro-inflammatory cytokines were significantly elevated, indicating that reduced Osx expression may reflect an inflammatory-prone state. In particular, the expression of interleukin-6, a key mediator of chronic inflammation, was increased in Osx heterozygotes and decreased in Osx overexpressing osteoblasts, and transcriptionally down-regulated by Osx. Although no significant differences were revealed in renal morphology and function between Osx heterozygotes and wild-type under normoxic conditions, recovery of kidneys after ischemic damage was remarkably delayed in Osx heterozygotes, as indicated by elevated blood urea nitrogen and creatinine levels, and by morphological alterations consistent with acute tubular necrosis. Eventually, protracted low Osx expression level caused an inflammatory-prone state in the body, resulting in the enhanced susceptibility to renal injury and the delayed renal repair after ischemia/reperfusion. This study suggests that the maintenance of Osx expression in bone is important in terms of preventing the onset of an inflammatory-prone state.

Highlights

Inflammation, which is classified as either acute or chronic, is part of the body’s defense mechanism that protects against damaging stimuli or infections and plays a central role in many diseases
Inflammatory-prone Condition in Osx Heterozygotes To investigate whether osteoblasts expressing low levels of Osx function normally in matrix mineralization and bone formation, in vivo and in vitro bone formation were examined in wild-type (Osxflox/+) and Osx heterozygous (Osxflox/2) mice
Cortical bone mineral density (BMD) and trabecular thickness (Tb.Th) were significantly decreased in Osx heterozygotes compared to wild-type, while other cortical or trabecular parameters were not considerably different between two groups (Fig. 1C)

Summary

Introduction

Inflammation, which is classified as either acute or chronic, is part of the body’s defense mechanism that protects against damaging stimuli or infections and plays a central role in many diseases. Whereas acute inflammation refers to the initial protective response to tissue injury, chronic inflammation refers to an imbalanced inflammatory response to tissue damage caused by persistent infections, prolonged exposure to potentially toxic agents, or autoimmunity. A chronic inflammatory mouse model with sickle cell disease is highly sensitive to renal I/R injury [3]. Chronic inflammation delays wound healing and increases scarring [4]. These observations indicate that the inflammatory-prone state can worsen the damage from I/R injury and can delay wound repair in a wide range of tissues

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