Browsing by Subject "Signal Transducer and Activator of Transcription 3"

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    The essential role of Stat3 in bone homeostasis and mechanotransduction
    (2014-05) Zhou, Hongkang; Li, Jiliang; Marrs, James; Stocum, David L.; Atkinson, Simon; Aguilar, R. Claudio; Yokota, Hiroki, 1955-
    Signal Transducer and Activator of Transcription 3 (Stat3) is a transcription factor expressed in bone and joint cells that include osteoblasts, osteocytes, osteoclasts, and chondrocytes. Stat3 is activated by a variety of cytokines and growth factors, including IL-6/gp130 family cytokines. These cytokines not only regulate the differentiation of osteoblasts and osteoclasts, but also regulate proliferation of chondrocytes through Stat3 activation. In 2007, mutations of Stat3 have been confirmed to cause a rare human immunodeficiency disease – Job syndrome which presents skeletal abnormalities like: reduced bone density (osteopenia), scoliosis, hyperextensibility of joints, and recurrent pathological bone fractures. Changes in the Stat3 gene alter the structure and function of the Stat3 proteins, impairing its ability to control the activity of other genes. However, little is known about the effects of Stat3 mutations on bone cells and tissues. To investigate the in vivo physiological role of Stat3 in bone homeostasis, osteoblast/osteocyte-specific Stat3 knockout (KO) mice were generated via the Cre-LoxP recombination system. The osteoblast/osteocyte-specific Stat3 KO mice showed bone abnormalities and an osteoporotic phenotype because of a reduced bone formation rate. Furthermore, inactivation of Stat3 decreased load-driven bone formation, and the disruption of Stat3 in osteoblasts suppressed load-driven mitochondrial activity, which led to an elevated level of reactive oxygen species (ROS) in cultured primary osteoblasts. Stat3 has been found to be responsive to mechanical stimulation, and might play an important role in mechanical signal transduction in osteocytes. To investigate the role Stat3 plays in mechanical signaling transduction, osteocyte-specific Stat3 knockout (KO) mice were created. Inactivation of Stat3 in osteocytes presented a significantly reduced load-driven bone formation. Decreased osteoblast activity indicated by reduced osteoid surface was also found in osteocyte-specific Stat3 KO mice. Moreover, sclerostin (SOST) protein which is a critical osteocyte-specific inhibitor of bone formation, its encoded gene SOST expression has been found to be enhanced in osteocyte-specific Stat3 KO mice. Thus, these results clearly demonstrated that Stat3 plays an important role in bone homeostasis and mechanotransduction, and Stat3 is not only involved in bone-formation-important genes regulation in the nucleus but also in mediation of ROS and oxidative stress in mitochondria.
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    Selective inactivation of Stat3 in osteoclasts affect bone mass differently in female and male mice
    (Office of the Vice Chancellor for Research, 2013-04-05) Himes, Evan; Zhou, Hongkang; Li, Jiliang
    Signal Transducer and Activator of Transcription 3 (Stat3) is activated by the binding of various cytokines to their receptors, such as IL-6. Previous studies have revealed that conditional knockouts of Stat3 in osteoblasts and osteocytes cause a decrease in bone mineral density and strength. To study the role of Stat3 in osteoclasts, osteoclast- specific knockout mice were created using cre-lox recombination. Bone mineral density (BMD) and bone mineral content (BMC) were calculated for femurs and the fourth lumbar vertebra (L4) of 8 weeks old mice. Analysis revealed a decrease in BMD of femurs of osteoclast-selective Stat3 knockout (KOOc-Stat3) mice compared to their littermate control (p<0.05). There was also a decrease in BMC of the femurs of KOOc-Stat3 mice compared to the littermate controls (p<0.05). Analysis of μCT data from trabecular bone in the distal femur showed significant decreases in trabecular number and bone volume/tissue volume in both male and female KOOc-Stat3 mice. Trabecular separation was increased in male and female KOOc-Stat3 mice. Bone histomorphometry at the distal femur revealed a significant decrease in bone formation rate in males and females KOOc-Stat3 mice compared to the littermate controls. Osteoclast number identified by tartrate resistant acid phosphatase (TRAP) stain in female KOOc-Stat3 mice was significantly deficient from their control. These data suggest that inactivation of Stat3 in osteoclasts influences bone metabolism through both osteoblasts and osteoclasts. Knockout of Stat3 in either cell type leads to decreases in bone strength, making Stat3 a good drug target for treatment of diseases such as osteoporosis.