Stat3 in osteocytes mediates osteogenic response to loading

Corry, Kylie A.; Zhou, Hongkang; Brustovetsky, Tatiana; Himes, Evan R.; Bivi, Nicoletta; Horn, M. Ryne; Kitase, Yukiko; Wallace, Joseph M.; Bellido, Teresita; Brustovetsky, Nickolay; Li, Jiliang

doi:10.1016/j.bonr.2019.100218

Cited by 26 publications

(32 citation statements)

References 54 publications

(60 reference statements)

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“…Histomorphometry was carried out as described previously 1,[17][18][19] . Bone specimens from mice were immersed in 10% neutral buffered formalin for 48 h. The specimens were then dehydrated in graded alcohols and methyl methacrylate, then embedded in methyl methacrylate with 4% of dibutyl phthalate and 0.25~0.8% of Perkadox × 16 3 .…”

Section: Histomorphometrymentioning

confidence: 99%

“…Micro computed tomography (μCT) analysis. The μCT scanning and analysis were carried out as described previously 1,[17][18][19] . Left femurs were scanned using micro-CT (μCT) (SkyScan 1172, Bruker-microCT, Kontich, Belgium), followed by reconstruction for conversion into individual cross-section slices using the SkyScan NRecon software (Bruker-microCT, Kontich, Belgium).…”

Section: Histomorphometrymentioning

confidence: 99%

“…Mechanical testing. The mechanical testing was carried out as described previously 1,[17][18][19] . The left femurs obtained from 18-week-old mice were tested via three-point bending and compression, respectively, following previously published protocols 20 .…”

Section: Histomorphometrymentioning

confidence: 99%

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Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Yin

Corry

Loughran

et al. 2020

Sci Rep

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Keap1 is a negative controller of the transcription factor Nrf2 for its activity. The Keap1/Nrf2 signaling pathway has been considered as a master regulator of cytoprotective genes, and exists in many cell types including osteoblasts and osteoclasts. Our previous study shows Nrf2 deletion decreases bone formation. Recent studies show hyperactivation of Nrf2 causes osteopenia in Keap1 −/− mice, and Keap1 −/− osteoblasts have significantly less proliferative potential than Keap1 +/− osteoblasts. We aimed to examine if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism. We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice. Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5a in cultured primary osteoblasts compared to WT control. In male mice, compared with their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone formation rate (+30.7%, P = 0.0029), but did not change the ultimate force (P < 0.01). The osteoclast cell numbers (−32.45%, p = 0.01) and surface (−32.58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice. Compared to male WT mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased. Our data suggest that moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling in male mice.

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Section: Histomorphometrymentioning

confidence: 99%

Section: Histomorphometrymentioning

confidence: 99%

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Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Yin

Corry

Loughran

et al. 2020

Sci Rep

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“…The JAK/STAT pathway not only appears to be involved in bone homeostasis and response but also in the differentiation processes of some cells type. In particular, even the cytokines involved in the signaling pathway activation can act on this variety of cells, for example on osteoblasts, osteoclasts and osteocytes [ 35 , 36 ]. The bone and the cells that regulate its remodeling are often subject to and/or influenced by the presence of cytokines belonging to the immune system.…”

Section: Jak/stat and Bone Cellsmentioning

confidence: 99%

JAK/STAT pathway and molecular mechanism in bone remodeling

et al. 2020

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JAK/STAT signaling pathway is involved in many diseases, including autoimmune diseases, which are characterized by a close interconnection between immune and bone system. JAK/STAT pathway is involved in bone homeostasis and plays an important role in proliferation and differentiation of some cell types, including osteoblasts and osteoclasts. Different molecules, such as cytokines, hormones, and growth factors are responsible for the activation of the JAK/STAT pathway, which leads, at the nuclear level, to start DNA transcription of target genes. Bone cells and remodeling process are often influenced by many cytokines, which act as strong stimulators of bone formation and resorption. Our aim, through careful research in literature, has been to provide an overview of the role of the JAK/STAT pathway in bone remodeling and on bone cells, with a focus on cytokines involved in bone turnover through this signal cascade. The JAK/STAT pathway, through the signal cascade activation mediated by the interaction with many cytokines, acts on bone cells and appears to be involved in bone remodeling process. However, many other studies are needed to completely understand the molecular mechanism underlying these bone process.

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“…In addition, mechanical strength and growth rate were reduced in osteoblast-specific STAT3 knock-out mice [20]. Load-driven bone formation after dynamic loading of the ulnae from osteoblast or osteocyte specific STAT3 knock-out mice was also decreased, while reactive oxygen species (ROS) levels increased, suggesting that STAT3 might regulate mitochondrial activity in osteoblasts [20,22].…”

Section: Introductionmentioning

confidence: 99%

The loss of STAT3 in mature osteoclasts has detrimental effects on bone structure

et al. 2020

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Signal Transducer and Activator of Transcription 3 (STAT3) has recently been shown to be involved in bone development and has been implicated in bone diseases, such as Job's Syndrome. Bone growth and changes have been known for many years to differ between sexes with male bones tending to have higher bone mass than female bones and older females tending to lose bone mass at faster rates than older males. Previous studies using conditional knock mice with Stat3 specifically deleted from the osteoblasts showed both sexes exhibited decreased bone mineral density (BMD) and strength. Using the Cre-Lox system with Cathepsin K promotor driving Cre to target the deletion of the Stat3 gene in mature osteoclasts (STAT3-cKO mice), we observed that 8-week old STAT3-cKO female femurs exhibited significantly lower BMD and bone mineral content (BMC) compared to littermate control (CN) females. There were no differences in BMD and BMC observed between male knockout and male CN femurs. However, micro-computed tomography (μCT) analysis showed that both male and female STAT3-cKO mice had significant decreases in bone volume/tissue volume (BV/TV). Bone histomorphometry analysis of the distal femur, further revealed a decrease in bone formation rate and mineralizing surface/ bone surface (MS/BS) with a significant decrease in osteoclast surface in female, but not male, STAT3-cKO mice. Profiling gene expression in an osteoclastic cell line with a knockdown of STAT3 showed an upregulation of a number of genes that are directly regulated by estrogen receptors. These data collectively suggest that regulation of STAT3 differs in male and female osteoclasts and that inactivation of STAT3 in osteoclasts affects bone turnover more in females than males, demonstrating the complicated nature of STAT3 signaling pathways in osteoclastogenesis. Drugs targeting the STAT3 pathway may be used for treatment of diseases such as Job's Syndrome and osteoporosis.

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Stat3 in osteocytes mediates osteogenic response to loading

Cited by 26 publications

References 54 publications

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice

JAK/STAT pathway and molecular mechanism in bone remodeling

The loss of STAT3 in mature osteoclasts has detrimental effects on bone structure

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