Persistent low level of osterix accelerates interleukin-6 production and impairs regeneration after tissue injury.
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.
Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea.
Wook-Young
WY
Baek
Seung-Yoon
SY
Park
Yeo Hyang
YH
Kim
Min-A
MA
Lee
Tae-Hwan
TH
Kwon
Kwon-Moo
KM
Park
Benoit
B
de Crombrugghe
Jung-Eun
JE
Kim
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D006579:Heterozygote; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007677:Kidney Function Tests; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D012038:Regeneration; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D015850:Interleukin-6; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors