Glucocorticoids and neonatal brain injury: the hedgehog connection

Gulino, Alberto; Smaele, Enrico De; Ferretti, Elisabetta

doi:10.1172/jci38387

Cited by 8 publications

(6 citation statements)

References 28 publications

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“…It is noteworthy that reactive astrocytes in an injured cerebral cortex can also produce and secrete the SHH protein, which can stimulate Oligo 2ϩ expressing progenitor cells (Amankulor et al, 2009 GCPs can give rise to mature oligodendrocytes that contribute to re-myelination of injured axons. These observations support the therapeutic interest of stimulating the SHH pathway for treating diverse brain defects and injuries, neurodegenerative disorders, and cerebral cortical injuries such as multiple sclerosis (Bambakidis et al, 2009;Gulino et al, 2009;Zhang et al, 2009). it has been shown that the SHH protein plays a critical role in coronary development and can promote the formation of coronary vessels in the embryonic and adult heart.…”

Section: Functions Of the Sonic Hedgehog Cascade In The Postnatal Devsupporting

confidence: 59%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Mimeault

Batra

2010

Pharmacological Reviews

105

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Section: Functions Of the Sonic Hedgehog Cascade In The Postnatal Devsupporting

confidence: 59%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Mimeault

Batra

2010

Pharmacological Reviews

105

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“…Very little is known about the effect of maternal corticosteroids on Shh, FGF10, and BMP4. Corticosteroids can inhibit Shh-mediated neural development and as such can have a detrimental effect on the neonatal developing brain (22). We found that maternal corticosteroids alone did not change the expression of these factors in the fetal lung compared with controls.…”

Section: Lps Exposure Leads To Changes In Shh Signaling In the Fetal mentioning

confidence: 55%

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

Collins

Kuypers

Nitsos

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin ( ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.

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“…It is well known that increased activity of the Ihh signaling pathway promotes chondrocyte proliferation (57) and mutation or disruption of Ihh signaling results in reduction of the height of the columnar layer in the growth plate (58). GCs are also known to suppresses Hh activity in neurons (59). All taken together, disruption of Hh signaling, whether it is through inhibition of Smo, using inhibitors or targeted deletion of Ihh, leads to growth plate fusion and bone growth impairment.…”

Section: Discussionmentioning

confidence: 99%

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

et al. 2019

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Glucocorticoids (GCs) are frequently used to treat chronic disorders in children, including inflammation and cancer. Prolonged treatment with GCs is well known to impair bone growth, an effect linked to increased apoptosis and suppressed proliferation in growth plate chondrocytes. We hypothesized that the endogenous antiapoptotic protein humanin (HN) may prevent these effects. Interestingly, GC‐induced bone growth impairment and chondrocyte apoptosis was prevented in HN overexpressing mice, HN‐treated wild‐type mice, and in HN‐treated cultured rat metatarsal bones. GC‐induced suppression of chondrocyte proliferation was also prevented by HN. Furthermore, GC treatment reduced Indian Hedgehog expression in growth plates of wild‐type mice but not in HN overexpressing mice or HN‐treated wild‐type animals. A Hedgehog (Hh) antagonist, vismodegib, was found to suppress the growth of cultured rat metatarsal bones, and this effect was also prevented by HN. Importantly, HN did not interfere with the desired anti‐inflammatory effects of GCs. We conclude that HN is a novel regulator of Hh signaling preventing GC‐induced bone growth impairment without interfering with desired effects of GCs. Our data may open for clinical studies exploring a new possible strategy to prevent GC‐induced bone growth impairment by cotreating with HN.—Zaman, F., Zhao, Y., Celvin, B., Mehta, H. H., Wan, J., Chrysis, D., Ohlsson, C, Fadeel, B., Cohen, P., Sävendahl, L. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment. FASEB J. 33, 4962–4974 (2019). http://www.fasebj.org

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Glucocorticoids and neonatal brain injury: the hedgehog connection

Cited by 8 publications

References 28 publications

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

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