Selective inhibition of Src family kinases by SU6656 increases bone mass by uncoupling bone formation from resorption in mice

Thouverey, Cyril; Ferrari, Serge; Caverzasio, Joseph

doi:10.1016/j.bone.2018.05.006

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…In a recent study, we confirmed that higher c-Src activity in mESCs reduces Runx2 nuclear localization and that PP2 and SrcI-1 increase intranuclear presence of Runx2 [36]. Cyril Thouverey et al showed that SU6656, a selective inhibitor of SFK increases osteoblast differentiation from MC3T3-E1 by inhibiting c-Src and Yes [6]. Zhang et al demonstrated that the differentiation-promoting activity of c-Src is antagonized by c-Yes in mES cells, despite their very close phylogenetic relationship [30].…”

Section: C-src Kinase Activity Inhibits Runx2 Nuclear Localizationsupporting

confidence: 67%

“…c-Src has been shown to increase the rate of bone resorption in mice [2,3] and to decrease osteoblast differentiation in vitro [4,5]. More recently, it was shown that inhibition of c-Src activity in adult mice increases bone mass at least in part by stimulating osteoblast differentiation [6]. However, while the inhibitory role of c-Src in osteogenesis has been studied, the role of c-Src in osteoblast differentiation of embryonic stem cells (ESCs) remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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c-Src kinase inhibits osteogenic differentiation via enhancing STAT1 stability

Alvandi

Opas

2020

PLoS ONE

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The proto-oncogene Src is ubiquitously expressed and is involved in cellular differentiation. However, the role of Src in embryonic stem (ES) cell osteogenic differentiation is largely unknown. Using the small molecule inhibitor PP2, c-Src specific siRNAs, and tet-inducible lentiviral vectors overexpressing active c-Src, we delineated an inhibitory role of c-Src in osteogenic differentiation of mouse embryonic stem cells (mESCs) and mouse MC3T3-E1s preosteoblasts. Active c-Src was shown to restrict the nuclear residency of Runt-related transcription factor 2 (Runx2) and its transcriptional activity with no detectable effect on Runx2 expression level. Furthermore, we showed Signal Transducer and Activator of Transcription 1 (STAT1) was indispensable to the inhibitory role of c-Src on Runx2 nuclear localization. Specifically, higher levels of active c-Src increased STAT1 half-life by inhibiting its proteasomal degradation, thereby increasing the cytoplasmic abundance of STAT1. More abundant cytoplasmic STAT1 bound and anchored Runx2, which restricted its nucleocytoplasmic shuttling and ultimately reduced Runx2 transcriptional activity. Collectively, this study has defined a new mechanism by which c-Src inhibits the transcriptional regulation of osteogenesis from mESCs in vitro.

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Section: C-src Kinase Activity Inhibits Runx2 Nuclear Localizationsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

c-Src kinase inhibits osteogenic differentiation via enhancing STAT1 stability

Alvandi

Opas

2020

PLoS ONE

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“…Src activity has been reported to maintain bone homeostasis and regulate cell invasion and growth [ 36 , 37 ]. Its class, tyrosine kinases, also affects the morphology, survival, and cell proliferation of osteoblasts [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Development of Cellular Signaling Pathways by Bioceramic Heat Treatment (Sintering) in Osteoblast Cells

Jung

Kim

Kim³

et al. 2023

Biomedicines

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Bioceramics are calcium-phosphate-based materials used in medical and dental implants for replacing or repairing damaged bone tissues; however, the effect of bioceramic sintering on the intracellular signaling pathways remains unknown. In order to address this, we analyzed the impact of sintering on the cell signaling pathways of osteoblast cells using sintered and non-sintered hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP). X-ray diffraction indicated that only the morphology of HA was affected by sintering; however, the sintered bioceramics were found to have elevated the calcium concentrations in relation to the non-sintered variants. Both bioceramics inhibited the JNK signaling pathway; the sintered HA exhibited half the value of the non-sintered variant, while the sintered β-TCP rarely expressed a p-JNK value. The total Src and Raptor protein concentrations were unaffected by the sintering, while the p-Src concentrations were decreased. The p-EGFR signaling pathway was regulated by the non-sintered bioceramics, while the p-p38 concentrations were reduced by both the sintered β-TCP and HA. All of the bioceramics attenuated the total AKT concentrations, particularly the non-sintered HA, and the AKT phosphorylation concentration, except for the non-sintered β-TCP. Thus, the sintering of bioceramics affects several intracellular signaling pathways. These findings may elucidate the bioceramic function and expand their application scope as novel substrates in clinical applications.

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“…Regulation of Src function is one of the targets of therapy for periodontal disease and other bone metabolic disease. Src inhibitor is one of the candidates of treatment [37].…”

Section: The Role Of Src In Osteoblasts and Osteocytesmentioning

confidence: 99%

A tyrosine kinase Src; regulator of bone homeostasis

Kokabu¹,

Matsubara²,

Yaginuma³

2019

Long-Term Survival of Patients With Ischemic Cardiomyopathy and Diabetes as Compared to Those Without Diabetes Undergoing Myoca

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The balance of bone formation by osteoblasts and bone resorption by osteoclasts is important for bone homeostasis. Pathologic high activity of osteoclasts and repression of bone osteoblastic bone formation result in bone metabolic diseases such as periodontal disease. To understand the mechanism of osteoblast and osteoclast function leads to establishment of therapy for bone metabolic disease. A tyrosine kinase Src deficient mice shows osteopetrosis because of defect bone resorbing activity and acceleration bone formation. This indicates Src is a key molecule to regulate bone resorption and bone formation. We discuss about the role of Src in osteoclast and osteoblast and entire bone metabolism.

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Selective inhibition of Src family kinases by SU6656 increases bone mass by uncoupling bone formation from resorption in mice

Cited by 5 publications

References 52 publications

c-Src kinase inhibits osteogenic differentiation via enhancing STAT1 stability

c-Src kinase inhibits osteogenic differentiation via enhancing STAT1 stability

Development of Cellular Signaling Pathways by Bioceramic Heat Treatment (Sintering) in Osteoblast Cells

A tyrosine kinase Src; regulator of bone homeostasis

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