title: Osteoblast/osteocyte-specific inactivation of Stat3 decreases load-driven bone formation and accumulates reactive oxygen species.
abstract: Signal transducers and activators of transcription 3 (Stat3) is a transcription factor expressed in many cell types including osteoblasts, osteocytes, and osteoclasts. STAT3 mutations cause a rare human immunodeficiency disease that presents reduced bone mineral density and recurrent pathological fractures. To investigate the role of Stat3 in load-driven bone metabolism, two strains of osteoblast/osteocyte-selective Stat3 knockout (KO) mice were generated. Compared to age-matched littermate controls, this selective inactivation of Stat3 significantly lowered bone mineral density (7-12%, p<0.05) as well as ultimate force (21-34%, p<0.01). In ulna loading (2.50-2.75N with 120 cycles/day at 2Hz for 3 consecutive days), Stat3 KO mice were less responsive than littermate controls as indicated by reduction in relative mineralizing surface (rMS/BS, 47-59%, p<0.05) and relative bone formation rate (rBFR/BS, 64-75%, p<0.001). Furthermore, inactivation of Stat3 suppressed load-driven mitochondrial activity, which led to an elevated level of reactive oxygen species (ROS) in cultured primary osteoblasts. Taken together, the results support the notion that the loss-of-function mutation of Stat3 in osteoblasts and osteocytes diminishes load-driven bone formation and impairs the regulation of oxidative stress in mitochondria.
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Hongkang
authors.initials: H
authors.lastname: Zhou
authors.forename: America B
authors.initials: AB
authors.lastname: Newnum
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Martin
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.forename: Akira
authors.initials: A
authors.lastname: Moh
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010011:Osteocytes / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013314:Stress, Mechanical
chemical_list: D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor