Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells

Blüml, Stephan; Friedrich, Martin; Lohmeyer, Tobias; Sahin, Emine; Saferding, Victoria; Brunner, Julia; Puchner, Antonia; Mandl, Péter; Niederreiter, Birgit; Smolen, Josef S; Schabbauer, Gernot; Redlich, Kurt

doi:10.1136/annrheumdis-2013-203486

Cited by 45 publications

(27 citation statements)

References 35 publications

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“…36 In recent studies, PTEN was identified as an important regulatory factor in RANKL-induced osteoclastogenesis. 37 Overexpression of PTEN inhibits RANKL-induced osteoclast formation by its negative regulation of RANKLinduced AKT and NF-κB signaling. 38 In a previous study, upregulated PTEN inhibited RANKL-induced PI3K/AKT activation.…”

Section: Discussionmentioning

confidence: 99%

<p>Lung Cancer Cells Derived Circulating miR-21 Promotes Differentiation of Monocytes into Osteoclasts</p>

Zhao¹,

Liu²,

Xie³

et al. 2020

OTT

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Osteoclastogenesis is a key process in osteolytic bone metastasis (BM). Previous studies indicated that some miRNAs could regulate cancers progression and osteoclastogenesis. Our purpose was to investigate the roles of lung cancer cells-derived circulating miR-21 on osteoclastogenesis and its clinical significance in BM patients. Materials and Methods: The difference of miRNA expression in two lung cancer cell lines SBC-5 (with characteristic BM ability) and SBC-3 (without BM ability) were analyzed by microarray and qRT-PCR. Circulating miR-21 levels of lung cancer patients with or without BM were compared by qRT-PCR. The TRAP staining was used to investigate the effects of conditioned media from lung cancer cell lines or patients' plasma with different miR-21 levels on osteoclastogenesis. ROC curve was used to evaluate the diagnostic performance of circulating miR-21 in BM patients. Results: We found that miR-21 expression was specifically higher in SBC-5 than that in SBC-3 cells. The supernatants of SBC-5 cells with higher-level miR-21 promoted osteoclastogenesis. Moreover, we demonstrated that the circulating miR-21 level was significantly higher in BM patients than that in non-BM patients. The plasma from BM patients with higher-level miR-21 could also promote osteoclastogenesis. Mechanistically, lung cancer cells-derived circulating miR-21 could be transferred into osteoclast precursor cells and promote osteoclastogenesis probably by inhibiting PTEN. Finally, clinical data showed that circulating miR-21 had a potential for the diagnosis of BM. Conclusion: Overall, our findings suggested that circulating miR-21 played important roles in osteoclastogenesis of lung cancer patients and may serve as a biomarker to diagnose BM of lung cancer.

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Section: Discussionmentioning

confidence: 99%

<p>Lung Cancer Cells Derived Circulating miR-21 Promotes Differentiation of Monocytes into Osteoclasts</p>

Zhao¹,

Liu²,

Xie³

et al. 2020

OTT

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“…In B cells from patients with SLE, increased levels of microRNA (miR)-7, miR-21 and miR-22 inhibit PTEN expression 91 . Loss of PTEN also increases the osteoclastogenic potential of myeloid cells, leading to enhanced local inflammation and bone destruction 92 .…”

Section: Biology Of Mtor Complexesmentioning

confidence: 99%

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

2015

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Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of Tfollicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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“…For example, PTEN has been found to specifically inhibit prostate cancer cell migration to boneconditioned medium, but not lung-conditioned medium in vitro [Wu et al, 2007]. Also, myeloid-specific Pten-null mice display increased osteoclastogenesis compared to wild-type mice [Bluml et al, 2015]. In this study, we showed that loss of Pten function using its inhibitor VO-OHpic increases tumor associated osteoclast differentiation in vitro.…”

Section: Discussionmentioning

confidence: 59%

PTEN Plays Dual Roles As a Tumor Suppressor in Osteosarcoma Cells

Chen

2017

J. Cell. Biochem.

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Osteosarcoma (OS) is the most common primary bone cancer, which occurs primarily in children and adolescents. Functional loss of the tumor suppressor PTEN has been demonstrated in bone malignancies including OS. We have recently reported that Pten expression inversely correlates with OS aggressiveness in mouse models. However, the mechanism whereby PTEN exerts its anti-tumor effect remains unknown. In this study, we first examined the expression of PTEN in human OS cell lines including U2OS, MG63 and Saos-2, and found that PTEN expression is reduced as compared to normal human osteoblasts. The downregulation of PTEN also associates with activation of AKT pathway. We then treated previously reported mouse OS tumor cells MOTO-Rank and human OS cell line U2OS with PTEN inhibitor VO-OHpic to investigate how PTEN impacts tumor cell behaviors. Our results showed that PTEN inhibits tumor cell proliferation, migration and invasion, but enhances tumor cell apoptosis. However, PTEN has no effects on tumor cell senescence and chemotaxis. PTEN also fails to induce tumor cells differentiation toward osteoblast lineage. On the other hand, PTEN inhibits tumor associated osteoclast differentiation. Moreover, overexpression of PTEN using gene transfer in U2OS cells inhibits proliferation but increases apoptosis. These findings indicate that PTEN not only targets tumor cells themselves by impacting cell behaviors, but also blocks osteoclast-mediated bone destruction, leading to interruption of the vicious cycle during osteosarcomagenesis. Loss of PTEN may consequently facilitate tumor growth and expansion in bone. Restoration of fully functional PTEN using gene therapy represents a potential approach against OS. J. Cell. Biochem. 118: 2684-2692, 2017. © 2017 Wiley Periodicals, Inc.

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Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells

Cited by 45 publications

References 35 publications

<p>Lung Cancer Cells Derived Circulating miR-21 Promotes Differentiation of Monocytes into Osteoclasts</p>

<p>Lung Cancer Cells Derived Circulating miR-21 Promotes Differentiation of Monocytes into Osteoclasts</p>

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

PTEN Plays Dual Roles As a Tumor Suppressor in Osteosarcoma Cells

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