The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo

Kim, Hyun Ju; Zhang, Kaihua; Zhang, Lihong; Ross, F. Patrick; Teitelbaum, Steven L.; Faccio, Roberta

doi:10.1073/pnas.0806963106

Cited by 46 publications

(43 citation statements)

References 46 publications

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“…Src Ϫ/Ϫ mice are osteopetrotic because of defective formation of ruffled borders and subsequent bone resorption but not because of impaired osteoclast differentiation (47), suggesting the existence of compensatory mechanisms by other Src family members in mice. Whereas a negative regulatory function of Lyn in osteoclastogenesis was reported (48), the expression of Fyn, another Src family member, increased during osteoclast differentiation (12). Our observations that 3BP2 is a partner and substrate of Fyn (21,23) therefore suggest that Fyn may participate in 3BP2 signaling in addition of Src.…”

Section: Discussionmentioning

confidence: 62%

3BP2 Adapter Protein Is Required for Receptor Activator of NFκB Ligand (RANKL)-induced Osteoclast Differentiation of RAW264.7 Cells

Guezguez

Prod’homme

Mouska

et al. 2010

Journal of Biological Chemistry

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The adapter protein 3BP2 (also known as SH3BP2 and Abl SH3-binding protein 2) has been involved in leukocyte signaling and activation downstream immunoreceptors. Genetic studies have further associated 3BP2 mutations to the human disease cherubism and to inflammation and bone dysfunction in mouse. However, how wild type 3BP2 functions in macrophage differentiation remains poorly understood. In this study, using small interfering RNA-mediated silencing of 3BP2 in the RAW264.7 monocytic cell line, we show that 3BP2 was required for receptor activator of NFB ligand (RANKL)-induced differentiation of RAW264.7 cells into multinucleated mature osteoclasts but not for granulocyte macrophage-colony stimulating factor/interleukin-4-induced differentiation into dendritic cells. 3BP2 silencing was associated with impaired activation of multiple signaling events downstream of RANK, including actin reorganization; Src, ERK, and JNK phosphorylation; and up-regulation of osteoclastogenic factors. In addition, 3BP2 knockdown cells induced to osteoclast by RANKL displayed a reduced increase of Src and nuclear factor of activated T cells (NFATc1) mRNA and protein expression. Importantly, 3BP2 interacted with Src, Syk, Vav, and Cbl in monocytic cells, and the introduction of constitutively active mutants of Src and NFATc1 in 3BP2-deficient cells restored osteoclast differentiation. Finally, the expression of a 3BP2 cherubism mutant was found to promote increased Src activity and NFAT-dependent osteoclast formation. Together, this study demonstrates that wild type 3BP2 is a key regulator of RANK-mediated macrophage differentiation into osteoclast through Src and NFATc1 activation.

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Section: Discussionmentioning

confidence: 62%

3BP2 Adapter Protein Is Required for Receptor Activator of NFκB Ligand (RANKL)-induced Osteoclast Differentiation of RAW264.7 Cells

Guezguez

Prod’homme

Mouska

et al. 2010

Journal of Biological Chemistry

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“…Indeed, in our experience total STAT5-KO BMMCs show only limited, yet significant, reduction in histamine and leukotriene B 4 release (9). It is notable, however, that the protein phosphatases SHP-1 and SHP-2 also associate with Gab2 (37), and that in another system, osteoclast development, Lyn complexes with Gab2 and SHP-1 (38). We hypothesize that the assemblage of these negative regulators with Gab2 contributes to the increase in Tyr(P)-STAT5 observed under the setting of a Gab2, SHP-1, or Lyn deficiency.…”

Section: Discussionmentioning

confidence: 94%

Novel Mechanism for FcϵRI-mediated Signal Transducer and Activator of Transcription 5 (STAT5) Tyrosine Phosphorylation and the Selective Influence of STAT5B over Mast Cell Cytokine Production

Pullen

Barnstein

Falanga

et al. 2012

Journal of Biological Chemistry

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Background: STAT5 is a transcription factor that is vital for mast cell function. Results: Loss of Fyn kinase prevents, whereas loss of Lyn, Gab2, or SHP-1 enhances, Fc⑀RI-mediated STAT5 tyrosine phosphorylation. Conclusion: IgE-mediated STAT5 activation in mast cells requires Fyn kinase.Significance: Elucidating the mechanisms of mast cell activity is essential to understanding and treating allergic pathologies.

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“…In each case, similar results were obtained, suggesting that we were indeed observing a real and reproducible effect. A possible explanation for the loss of the effect with increasing dose could be the inhibition of other kinases such as Abl or Lyn, whose osteopenic knockout phenotypes (Li et al, 2000;Kim et al, 2009) would predict a negative effect on bone upon pharmacological inhibition. Fur- thermore, it is perhaps relevant that compound I had biphasic effects in the hMSC assay (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to Src, a number of other kinases have been implicated in bone cell physiology (Li et al, 2000;Buckbinder et al, 2007;Kim et al, 2009Kim et al, , 2010. Of particular interest to us was Abl, whose knockout had osteopenic bones due to a failure of osteoblast differentiation (Li et al, 2000), and which is often nonselectively inhibited by Src inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse

Murrills¹,

Fukayama²,

Boschelli³

et al. 2011

J Pharmacol Exp Ther

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Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Ablnull mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC 50 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (Ն0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 M compound I revealed downregulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide, ␤ (␤-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by ␤-CGRP.

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The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo

Cited by 46 publications

References 46 publications

3BP2 Adapter Protein Is Required for Receptor Activator of NFκB Ligand (RANKL)-induced Osteoclast Differentiation of RAW264.7 Cells

3BP2 Adapter Protein Is Required for Receptor Activator of NFκB Ligand (RANKL)-induced Osteoclast Differentiation of RAW264.7 Cells

Novel Mechanism for FcϵRI-mediated Signal Transducer and Activator of Transcription 5 (STAT5) Tyrosine Phosphorylation and the Selective Influence of STAT5B over Mast Cell Cytokine Production

Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse

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