Inhibition of STAT1 accelerates bone fracture healing.
Skeletal fracture healing involves a variety of cellular and molecular events; however, the mechanisms behind these processes are not fully understood. In the current study, we investigated the potential involvement of the signal transducer and activator of transcription 1 (STAT1), a critical regulator for both osteoclastogenesis and osteoblast differentiation, in skeletal fracture healing. We used a fracture model and a cortical defect model in mice, and found that fracture callus remodeling and membranous ossification are highly accelerated in STAT1-deficient mice. Additionally, we found that STAT1 suppresses Osterix transcript levels and Osterix promoter activity in vitro, indicating the suppression of Osterix transcription as one of the mechanisms behind the inhibitory effect of STAT1 on osteoblast differentiation. Furthermore, we found that fludarabine, a potent STAT1 inhibitor, significantly increases bone formation in a heterotopic ossification model. These results reveal previously unknown functions of STAT1 in skeletal homeostasis and may have important clinical implications for the treatment of skeletal bone fracture.
Tajima
Kosuke
K
Department of Orthopaedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
Takaishi
Hironari
H
Takito
Jiro
J
Tohmonda
Takahide
T
Yoda
Masaki
M
Ota
Norikazu
N
Kosaki
Naoto
N
Matsumoto
Morio
M
Ikegami
Hiroyasu
H
Nakamura
Toshiyasu
T
Kimura
Tokuhiro
T
Okada
Yasunori
Y
Horiuchi
Keisuke
K
Chiba
Kazuhiro
K
Toyama
Yoshiaki
Y
D000818:Animals; D002146:Bony Callus / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D013978:Tibial Fractures / Q000188:drug therapy* / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D050659:Core Binding Factor Alpha 1 Subunit; D004791:Enzyme Inhibitors; C493716:Runx2 protein, mouse; D050794:STAT1 Transcription Factor; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; C494080:Stat1 protein, mouse; D014157:Transcription Factors; D014740:Vidarabine; C024352:fludarabine