STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription

Yang, Yiling; Chung, Mi Ri; Zhou, Siru; Gong, Xiangyang; Xu, Hongyuan; Hong, Yueyang; Jin, Anting; Huang, Xiangru; Zou, Weiguo; Dai, Qinggang; Jiang, Lingyong

doi:10.1074/jbc.ra119.010139

Cited by 81 publications

(77 citation statements)

References 38 publications

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“…Various studies have examined the functions of STAT3 in osteoclasts in bone formation and maintenance, including studies which suggest that STAT3 acting downstream of RANKL mediates osteoclast differentiation [23,24,36]. In a mouse study using a conditional knock out of STAT3 with the TIE2-Cre, in which the Cre recombinase is driven by the endothelial-specific promoter/enhancer and is thought to be expressed during an early stage of hematopoietic cell lineage, Zhang et al [24] reported that the loss of STAT3 resulted in mice with an increased osteoclast number and activity with a severe osteoporosis phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, also with conditional knock-out of STAT3 in osteoclasts using a cathepsin promoter driving Cre recombinase, Yang et al [ 23 ] showed that the STAT3 conditional knock-out mice exhibited an increase in bone mass of the 20 weeks old mice in comparison with control mice, the Stat3 LoxP/LoxP ; Cstk-Cre(-) mice. This observation is opposite to our current finding.…”

Section: Discussionmentioning

confidence: 99%

“…In the Yang et al study [23], the downstream targets of STAT3 signaling were examined using cell culture treated with AG490 in an attempt to inhibit STAT3 signaling. A critical factor that one must consider when using JAK2 kinase inhibitors such as AG490 is that it is a very strong inhibitor, but lacks target specificity and thus, it might also downregulate other STAT proteins.…”

Section: Plos Onementioning

confidence: 99%

“…While the functions of STAT3 in osteoblasts and osteocytes are emerging, the roles of STAT3 in osteoclasts have not been clearly defined. A recent study in which STAT3 in osteoclasts was deleted by use of the Cathepsin K promoter driving Cre recombinase demonstrated that mice exhibited an increase in BMD with a decrease in bone resorption [23]. However, mice in which STAT3 was conditionally deleted using TIE2 promoter driving Cre in early stages of osteoclast development exhibited osteoporosis with significantly higher osteoclast numbers [24].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…TNF-α, IL-1β, IL-6 IL-7, and IL-15 can also induce the expression of M-CSF or RANKL [ 70 , 71 ]. Nevertheless, there are some discrepancies in the literature regarding the role played by some ILs, such as IL-6, during osteoclastogenesis [ 72 , 73 , 74 ]. For example, IL-6 (100 ng/mL) appears to suppress the osteoclast progenitor differentiation induced by M-CSF plus soluble RANKL (100 ng/mL) in vitro [ 73 ].…”

Section: Osteoblast/osteoclast Balance In Bone Remodeling and Repamentioning

confidence: 99%

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

Jann

Gascon

Roux

et al. 2020

IJMS

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The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors—in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins—not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated.

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Fat Extract Modulates Calcium Signaling and Protects against Hyperactive Osteoclastogenesis in Bone Remodeling with Antioxidant Capacity

Yang

Kan

et al. 2023

Advanced Therapeutics

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Osteoclasts are cells primarily involved in bone remodeling. Hyperactive osteoclastogenesis leads to pathological bone loss and microarchitectural deterioration. However, given the limitations of current osteoclast inhibitors, there is an urgent need for a novel antiresorptive agent with higher efficiency and fewer side effects. Cell‐free fat extract (CEFFE) is the liquid fraction obtained from adipose tissues, which are enriched with a variety of adipokines. This study aims to explore its pharmacologic effect on hyperactive osteoclastogenesis. CEFFE exhibits excellent potentials to attenuate osteoclast‐associated bone loss in ovariectomy mice and to inhibit osteoclastogenesis in primary monocytes. Furthermore, the cationic protein fraction of CEFFE (CEFFE‐Cation) is identified as the main inhibitory component in osteoclast formation assay. According to liquid chromatography with tandem mass spectrometry analysis, the CEFFE‐Cation fraction mainly consists of various antioxidant enzymes and cytokines, which endow it with a superior antioxidant capacity. Meanwhile, CEFFE‐Cation is also capable of mitigating Ca2+ oscillation and subsequent nuclear factor of activated T‐cells 1 nuclear translocation during osteoclastogenesis. Overall, this study elucidates the promising translational potential of CEFFE as a next‐generation personalized antiresorptive agent for osteolytic bone disease treatment.

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STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription

Cited by 81 publications

References 38 publications

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

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

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

Fat Extract Modulates Calcium Signaling and Protects against Hyperactive Osteoclastogenesis in Bone Remodeling with Antioxidant Capacity

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