Stat3 in osteocytes mediates osteogenic response to loading
Kylie A. Corry,
Hongkang Zhou,
Tatiana Brustovetsky,
Evan R. Himes,
Nicoletta Bivi,
M. Ryne Horn,
Yukiko Kitase,
Joseph M. Wallace,
Teresita Bellido,
Nickolay Brustovetsky,
Jiliang Li
Affiliations
Kylie A. Corry
Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Hongkang Zhou
Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Tatiana Brustovetsky
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Evan R. Himes
Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Nicoletta Bivi
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
M. Ryne Horn
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Yukiko Kitase
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Joseph M. Wallace
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
Teresita Bellido
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush Veterans Administration Medical Center
Nickolay Brustovetsky
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Jiliang Li
Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Corresponding author at: Department of Biology, Indiana University Purdue University Indianapolis, 723 W Michigan Street, SL306, Indianapolis, IN 46202, USA.
Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat family of proteins involved in signaling in many different cell types, including osteocytes. Osteocytes are considered major mechanosensing cells in bone due to their intricate dendritic networks able to sense changes in physical force and to orchestrate the response of osteoclasts and osteoblasts. We examined the role of Stat3 in osteocytes by generating mice lacking Stat3 in these cells using the Dmp-1(8kb)-Cre promoter (Stat3cKO mice). Compared to age-matched littermate controls, Stat3cKO mice of either sex (18 weeks old) exhibit reduced bone formation indices, decreased osteoblasts and increased osteoclasts, and altered material properties, without detectable changes in bone mineral density (BMD) or content of either trabecular or cortical bone. In addition, Stat3cKO mice of either sex show significantly decreased load-induced bone formation. Furthermore, pharmacologic inhibition of Stat3 in osteocytes in vitro with WP1066 blocked the increase in cytosolic calcium induced by ATP, a mediator of the cellular responses to sheer stress. WP1066 also increased reactive oxygen species (ROS) production in cultured MLO-Y4 osteocytes. These data demonstrate that Stat3 is a critical mediator of mechanical signals received by osteocytes and suggest that osteocytic Stat3 is a potential therapeutic target to stimulate bone anabolism. Keywords: Signal transducers and activators of transcription 3 (Stat3), Mechanotransduction, Osteocyte, ROS, ATP, Bone formation