TGF-β1 impairs mechanosensation of human osteoblasts via HDAC6-mediated shortening and distortion of primary cilia

Ehnert, Sabrina; Sreekumar, Vrinda; Aspera-Werz, Romina H.; Sajadian, Sahar Olsadat; Wintermeyer, Elke; Sandmann, Gunther H.; Bahrs, Christian; Hengstler, Jan G.; Godoy, Patrício; Nüssler, Andreas K.

doi:10.1007/s00109-017-1526-4

Cited by 47 publications

(50 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with our previous study, basal expression levels were in descending order: HDAC2, -5, -7, -3, -1, -9, -8, -4, and -6. Basal expression levels of HDAC11 and -10 were close to the detection limit [27]. During the osteogenic differentiation process, 75% of the HDACs expressed were the isoforms HDAC2 (42.4%), HDAC5 (21.3%), and HDAC7 (12.0%).…”

Section: Stimulation With Rhtgf-β 1 Alters Hdac Expression In Hobsmentioning

confidence: 53%

“…In our group, we could show that the upregulation of HDAC6 results in shortened and deformed primary cilia, which impairs the mechanically driven osteogenesis [27]. Besides the increased expression of these HDACs, the expression of HDAC9 was significantly reduced.…”

Section: Rhtgf-β 1 Treatment Significantly Downregulated Hdac9 Expresmentioning

confidence: 77%

“…This is described for HDAC1 and -3 overexpression, which inhibits the expression of the key osteogenic transcription factor Runx2 [20][21][22]. Furthermore, the overexpression of HDAC6 causes a de-acetylation of α-tubulin, resulting in damaged primary cilia and impaired mechanically driven osteogenesis [27]. Conversely, HDAC4, -5, -6, -7, and -8 have been described to bind Runx2 and thus interfere with its transcriptional activity [23][24][25][26].…”

Section: Discussionmentioning

confidence: 96%

“…Runx2 transcriptional activity is reduced by the binding of class II HDACs (HDAC4, -5, -6, and -7) to Runx2 [23][24][25][26]. In addition, enhanced expression of HDAC6 causes deacetylation of α-tubulin, causing a shortening and distortion of the cells primary cilia (mechanosensors) and thus impairing mechanically driven osteogenesis [27]. The expression of HDAC9, which plays a crucial role in immunity, is reported to negatively correlate with osteoclastogenesis [28].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

Ehnert¹,

Heuberger²,

Nüssler³

et al. 2017

JFMK

Self Cite

View full text Add to dashboard Cite

Abstract:Transforming growth factor β (TGF-β) is a key regulator of bone density. Recently, we have shown that TGF-β 1 effectively blocks bone morphogenetic protein-induced maturation of human osteoblasts (hOBs) in a histone deacetylase (HDAC)-dependent manner. To better understand the underlying mechanisms and to identify possible therapeutic targets, the current study aimed at characterizing the expression changes of different HDACs in hOBs following recombinant human TGF-β 1 treatment and investigating the effect of the altered HDACs on both the proliferation and maturation of hOBs and osteogenic cell lines. As expected from our previous work, exposure to rhTGF-β 1 induced the expression of HDACs (HDAC1, -2, -3, -6). However, to our surprise, rhTGF-β 1 treatment strongly suppressed the expression of HDAC9 during osteogenic differentiation. HDAC9 is reported to suppress osteoclastogenesis; however, little is known about the role of HDAC9 in osteogenesis. Chemical inhibition of HDAC9 with TMP269 increased cell numbers of hOBs, but significantly decreased their osteogenic function (alkaline phosphatase activity and matrix mineralization). In osteogenic cell lines (MG-63, CAL-72 and SAOS-2), the expression of HDAC9 negatively correlates with their proliferation capacity and positively correlates with their osteogenic differentiation potential. Being able to boost osteoclasts while inhibiting osteoblasts makes HDAC9 an interesting therapeutic target to support fracture healing and bone metabolisms.Keywords: primary human osteoblasts (phOBs); transforming growth factor β 1 (TGF-β 1 ); histone deacetylase 9 (HDAC9)

show abstract

Section: Stimulation With Rhtgf-β 1 Alters Hdac Expression In Hobsmentioning

confidence: 53%

Section: Rhtgf-β 1 Treatment Significantly Downregulated Hdac9 Expresmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

Ehnert¹,

Heuberger²,

Nüssler³

et al. 2017

JFMK

Self Cite

View full text Add to dashboard Cite

show abstract

“…Osteoblasts and osteoclasts secrete TGF-β in their latent form, which is then incorporated into the bone matrix [10,11]. Once released and activated during the bone turnover or fracture, active TGF-β has been reported to critically regulate maintenance and expansion of mesenchymal stem/stromal cells, as well as the differentiation of osteoprogenitor cells [12,13,14], which express a large variety of high-affinity TGF-β receptors [11]. Thus, many osteoblastic functions, e.g., chemoattraction, migration, proliferation, and collagen expression, are thought to be regulated by the canonical (often Smad3-dependent) TGF-β signaling [11,12].…”

Section: Introductionmentioning

confidence: 99%

Immune Cell Induced Migration of Osteoprogenitor Cells Is Mediated by TGF-β Dependent Upregulation of NOX4 and Activation of Focal Adhesion Kinase

Ehnert¹,

Aspera-Werz²,

Bykova³

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

The cytokines secreted by immune cells have a large impact on the tissue, surrounding a fracture, e.g., by attraction of osteoprogenitor cells. However, the underlying mechanisms are not yet fully understood. Thus, this study aims at investigating molecular mechanisms of the immune cell-mediated migration of immature primary human osteoblasts (phOBs), with transforming growth factor beta (TGF-β), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and focal adhesion kinase (FAK) as possible regulators. Monocyte- and macrophage (THP-1 cells ± phorbol 12-myristate 13-acetate (PMA) treatment)-conditioned media, other than the granulocyte-conditioned medium (HL-60 cells + dimethyl sulfoxide (DMSO) treatment), induce migration of phOBs. Monocyte- and macrophage (THP-1 cells)-conditioned media activate Smad3-dependent TGF-β signaling in the phOBs. Stimulation with TGF-β promotes migration of phOBs. Furthermore, TGF-β treatment strongly induces NOX4 expression on both mRNA and protein levels. The associated reactive oxygen species (ROS) accumulation results in phosphorylation (Y397) of FAK. Blocking TGF-β signaling, NOX4 activity and FAK signaling effectively inhibits the migration of phOBs towards TGF-β. In summary, our data suggest that monocytic- and macrophage-like cells induce migration of phOBs in a TGF-β-dependent manner, with TGF-β-dependent induction of NOX4, associated production of ROS and resulting activation of FAK as key mediators.

show abstract

Mechanosensation Mediates Long‐Range Spatial Decision‐Making in an Aneural Organism

et al. 2021

View full text Add to dashboard Cite

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, it is revealed that Physarum can use mechanosensation to reliably make decisions about distant objects in its environment, preferentially growing in the direction of heavier, substratedeforming, but chemically inert masses. This long-range sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or the addition of an inhibitor of mechanosensitive transient receptor potential channels. Additionally, it is demonstrated that Physarum does not respond to the absolute magnitude of strain. Computational modeling reveales that Physarum may perform this calculation by sensing the fraction of its perimeter that is distorted above a threshold substrate strain-a fundamentally novel method of mechanosensation. Using its body as both a distributed sensor array and computational substrate, this aneural organism leverages its unique morphology to make long-range decisions. Together, these data identify a surprising behavioral preference relying on biomechanical features and quantitatively characterize how the Physarum exploits physics to adaptively regulate its growth and shape.

show abstract

TGF-β1 impairs mechanosensation of human osteoblasts via HDAC6-mediated shortening and distortion of primary cilia

Cited by 47 publications

References 52 publications

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts

Immune Cell Induced Migration of Osteoprogenitor Cells Is Mediated by TGF-β Dependent Upregulation of NOX4 and Activation of Focal Adhesion Kinase

Mechanosensation Mediates Long‐Range Spatial Decision‐Making in an Aneural Organism

Contact Info

Product

Resources

About