Endogenously Produced Indian Hedgehog Regulates TGFβ-Driven Chondrogenesis of Human Bone Marrow Stromal/Stem Cells

Handorf, Andrew M.; Chamberlain, Connie S.; Li, Wan‐Ju

doi:10.1089/scd.2014.0266

Cited by 19 publications

(17 citation statements)

References 47 publications

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“…As Gli1 is a known target of hedgehog signaling activation this response was used as a positive control. This is consistent with previous work in a chondrogenesis model using human bone marrow stromal/stem cells (Handorf et al, 2015 ).…”

Section: Resultssupporting

confidence: 93%

Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets

et al. 2017

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Loss-of-function mutations in GLI3 and IHH cause craniosynostosis and reduced osteogenesis, respectively. In this study, we show that Ihh ligand, the receptor Ptch1 and Gli transcription factors are differentially expressed in embryonic mouse calvaria osteogenic condensations. We show that in both Ihh−/− and Gli3Xt−J/Xt−J embryonic mice, the normal gene expression architecture is lost and this results in disorganized calvarial bone development. RUNX2 is a master regulatory transcription factor controlling osteogenesis. In the absence of Gli3, RUNX2 isoform II and IHH are upregulated, and RUNX2 isoform I downregulated. This is consistent with the expanded and aberrant osteogenesis observed in Gli3Xt−J/Xt−J mice, and consistent with Runx2-I expression by relatively immature osteoprogenitors. Ihh−/− mice exhibited small calvarial bones and HH target genes, Ptch1 and Gli1, were absent. This indicates that IHH is the functional HH ligand, and that it is not compensated by another HH ligand. To decipher the roles and potential interaction of Gli3 and Ihh, we generated Ihh−/−;Gli3Xt−J/Xt−J compound mutant mice. Even in the absence of Ihh, Gli3 deletion was sufficient to induce aberrant precocious ossification across the developing suture, indicating that the craniosynostosis phenotype of Gli3Xt−J/Xt−J mice is not dependent on IHH ligand. Also, we found that Ihh was not required for Runx2 expression as the expression of RUNX2 target genes was unaffected by deletion of Ihh. To test whether RUNX2 has a role upstream of IHH, we performed RUNX2 siRNA knock down experiments in WT calvarial osteoblasts and explants and found that Ihh expression is suppressed. Our results show that IHH is the functional HH ligand in the embryonic mouse calvaria osteogenic condensations, where it regulates the progression of osteoblastic differentiation. As GLI3 represses the expression of Runx2-II and Ihh, and also elevates the Runx2-I expression, and as IHH may be regulated by RUNX2 these results raise the possibility of a regulatory feedback circuit to control calvarial osteogenesis and suture patency. Taken together, RUNX2-controlled osteoblastic cell fate is regulated by IHH through concomitant inhibition of GLI3-repressor formation and activation of downstream targets.

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Section: Resultssupporting

confidence: 93%

Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets

et al. 2017

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“… 8 Among the four most strongly up-regulated genes was Indian Hedgehog ( Ihh ), which is involved in cellular signalling, cartilage degeneration, and in TGFβ-driven processes. 23 , 24 Aircraft noise during the sleep phase increased vascular Ihh gene expression to a greater extent than exposure during the awake phase in accordance with an increase in Ihh in aorta of mice exposed for 4 days to around-the-clock noise (see Supplementary material online , Figure S11A ). The markers of endothelial cell activation and inflammation, Nos2 and Vcam1 , were increased at the mRNA level in cardiac tissue, mostly of sleep phase or around-the-clock noise exposed mice (see Supplementary material online , Figure S11B and C ), supporting the recently reported inflammatory phenotype in vessels of aircraft noise-exposed animals.…”

Section: Resultsmentioning

confidence: 69%

Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation

Kröller‐Schön

Daiber

Steven

et al. 2018

European Heart Journal

168

248

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AimsAircraft noise causes endothelial dysfunction, oxidative stress, and inflammation. Transportation noise increases the incidence of coronary artery disease, hypertension, and stroke. The underlying mechanisms are not well understood. Herein, we investigated effects of phagocyte-type NADPH oxidase (Nox2) knockout and different noise protocols (around-the-clock, sleep/awake phase noise) on vascular and cerebral complications in mice.Methods and resultsC57BL/6j and Nox2−/− (gp91phox−/−) mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)) around-the-clock or during sleep/awake phases for 1, 2, and 4 days. Adverse effects of around-the-clock noise on the vasculature and brain were mostly prevented by Nox2 deficiency. Around-the-clock aircraft noise of the mice caused the most pronounced vascular effects and dysregulation of Foxo3/circadian clock as revealed by next generation sequencing (NGS), suggesting impaired sleep quality in exposed mice. Accordingly, sleep but not awake phase noise caused increased blood pressure, endothelial dysfunction, increased markers of vascular/systemic oxidative stress, and inflammation. Noise also caused cerebral oxidative stress and inflammation, endothelial and neuronal nitric oxide synthase (e/nNOS) uncoupling, nNOS mRNA and protein down-regulation, and Nox2 activation. NGS revealed similarities in adverse gene regulation between around-the-clock and sleep phase noise. In patients with established coronary artery disease, night-time aircraft noise increased oxidative stress, and inflammation biomarkers in serum.ConclusionAircraft noise increases vascular and cerebral oxidative stress via Nox2. Sleep deprivation and/or fragmentation caused by noise triggers vascular dysfunction. Thus, preventive measures that reduce night-time aircraft noise are warranted.

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“…Yipee-like 2 (YPEL2) is localized in the nucleus and contains several metal binding sites, it is known to interact with phosphatases and influences calcium signaling in cellular repolarization ( 11 ). Indian hedgehog (IHH) is involved in signaling and has been found among other pathways to participate in cartilage degeneration as well as in TGFβ-driven chondrogenesis and ossification ( 99 , 263 ). Sacsin is highly expressed in the central nervous tissue and also shows abundant expression in fibrous tissue.…”

Section: Effects Of Noise On Vascular Function and Oxidative Strmentioning

confidence: 99%

The Adverse Effects of Environmental Noise Exposure on Oxidative Stress and Cardiovascular Risk

Münzel

Sørensen

Schmidt

et al. 2018

Antioxidants & Redox Signaling

187

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Epidemiological studies have provided evidence that traffic noise exposure is linked to cardiovascular diseases such as arterial hypertension, myocardial infarction, and stroke. Noise is a nonspecific stressor that activates the autonomous nervous system and endocrine signaling. According to the noise reaction model introduced by Babisch and colleagues, chronic low levels of noise can cause so-called nonauditory effects, such as disturbances of activity, sleep, and communication, which can trigger a number of emotional responses, including annoyance and subsequent stress. Chronic stress in turn is associated with cardiovascular risk factors, comprising increased blood pressure and dyslipidemia, increased blood viscosity and blood glucose, and activation of blood clotting factors, in animal models and humans. Persistent chronic noise exposure increases the risk of cardiometabolic diseases, including arterial hypertension, coronary artery disease, diabetes mellitus type 2, and stroke. Recently, we demonstrated that aircraft noise exposure during nighttime can induce endothelial dysfunction in healthy subjects and is even more pronounced in coronary artery disease patients. Importantly, impaired endothelial function was ameliorated by acute oral treatment with the antioxidant vitamin C, suggesting that excessive production of reactive oxygen species contributes to this phenomenon. More recently, we introduced a novel animal model of aircraft noise exposure characterizing the underlying molecular mechanisms leading to noise-dependent adverse oxidative stress-related effects on the vasculature. With the present review, we want to provide an overview of epidemiological, translational clinical, and preclinical noise research addressing the nonauditory, adverse effects of noise exposure with focus on oxidative stress. Antioxid. Redox Signal. 28, 873–908.

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Endogenously Produced Indian Hedgehog Regulates TGFβ-Driven Chondrogenesis of Human Bone Marrow Stromal/Stem Cells

Cited by 19 publications

References 47 publications

Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets

Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets

Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation

The Adverse Effects of Environmental Noise Exposure on Oxidative Stress and Cardiovascular Risk

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