BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

Hernandez, Humberto; Millar, J. A.; Curry, Stacy; Clark, Abbot F.; McDowell, Colleen M

doi:10.1167/iovs.17-23282

Cited by 31 publications

(31 citation statements)

References 72 publications

(118 reference statements)

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“…BAMBI was a TGF-β pseudoreceptor ,and down-regulation of BAMBI made HSCs beccome more sensitive to TGF-β [18], that was the main mechanism of endotoxin-induced hepatic brosis [19,20]. HSCs was the naïve cells that responds to LPS by TLR4 [21], BAMBI was down-regulated after TLR4-MyD88-NF-κB pathway was activated in HSCs [22].…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: The extract of a Traditional Chinese Medicine alleviates Hepatic Fibrosis of Rats by inhibiting NF-κB activation and upregulating BAMBI in Hepatic Stellate Cells

Li¹,

Tang²,

Lv³

et al. 2020

Preprint

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Background DaHuangZheChong pill (DHZCP) is a formula of traditional Chinese medicine, which has been written into the guideline for the prevention and treatment of hepatic fibrosis in China. The study was aim to investigate the anti-fibrotic effects and the potential mechanisms of DHZCP revolving around the TGF-β pseudo receptor, bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) in hepatic stellate cells (HSCs). Materials and Methods Wistar rats were given with CCL4 for four weeks to establish hepatic fibrosis model. Then the rats were given normal saline or DHZCP decoction six weeks. the pathology of liver tissue was analyzed, the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), BAMBI, and NF-κB were detected. In vitro, the associated signal molecules about LPS-activated NF-κB were also analyzed by immunohistochemistry, western blot, or electrophoretic mobility shift assay (EMSA) in cultured HSC-T6 cells . Results The DHZCP showed significant effects on improving fibrosis stage of liver tissue and inhibiting primary HSCs activation. The protein expression of TLR4/MyD88 was lower (P was both < 0.05), BAMBI was higher in DHZCP group than model control (MC) group (P < 0.05) in primary HSCs. In HSC-T6 cells, the activity of NF-κB was lower (P < 0.001), and BAMBI was higher (P < 0.05) in DHZCP added LPS group than in LPS group. Conclusion These results suggested that DHZCP alleviates hepatic fibrosis that was maybe associated with inhibiting activation of NF-κB induced by LPS, and upregulating BAMBI expression in HSCs.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: The extract of a Traditional Chinese Medicine alleviates Hepatic Fibrosis of Rats by inhibiting NF-κB activation and upregulating BAMBI in Hepatic Stellate Cells

Li¹,

Tang²,

Lv³

et al. 2020

Preprint

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“…Ad5.Null virus (Vector Biolabs, Malvern, PA, USA) was used as a negative control. Briefly, 2 μL of 2.5 × 10 7 plaque-forming units (pfu) was intravitreally injected into one eye, and the uninjected contralateral eyes were used as negative controls as previously described 13,15 . intraocular pressure Measurements.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, the ECM composition of the TM is important in regulating aqueous humor outflow and forming a fluid flow pathway for proper aqueous humor drainage 9,10 . It is also known that POAG patients have an increased accumulation of ECM proteins within the TM 11,12 , increased ECM production leads to an increase in aqueous humor (AH) outflow resistance 13 , decreases AH outflow facility [14][15][16][17][18] , and causes ocular hypertension 13,15,19,20 .…”

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confidence: 99%

“…The transforming growth factor beta 2 (TGFβ2) signaling pathway has been well studied in the TM and it is known to be elevated in the aqueous humor and TM tissue of glaucomatous eyes [23][24][25][26] . TGFβ2 has also been shown to mediate fibrosis development and ECM deposition within the TM, and induce ocular hypertension in both mice and in ex vivo perfusion organ culture systems 13,15,20,27,28 . We and others have also shown that TGFβ2 signals through both the canonical SMAD pathway, alters the ECM in human TM cells [29][30][31][32][33][34][35] , is essential for TGFβ2-induced ocular hypertension in mice 36 , and has the ability to crosstalk with TLR4 signaling 13,15 .…”

mentioning

confidence: 99%

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Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling

Roberts

Mavlyutov

Perlmutter

et al. 2020

Sci Rep

Self Cite

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Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage, which leads to impaired aqueous humor outflow. Here, we explore a novel molecular mechanism involved in glaucomatous TM damage. We investigated the role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA (FN-EDA), in TGFβ2-induced ocular hypertension in mice. We utilized transgenic mouse strains that either constitutively express only FN containing the EDA isoform or contain an EDA-null allele and express only FN lacking EDA, with or without a mutation in Tlr4, in our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2. IOP was measured over time and eyes accessed by immunohistochemistry for total FN and FN-EDA expression. Constitutively active EDA caused elevated IOP starting at 14 weeks of age. Ad5.TGFβ2 induced ocular hypertension in wildtype C57BL/6J mice and further amplified the IOP in constitutively active EDA mice. TLR4 null and EDA null mice blocked Ad5.TGFβ-induced ocular hypertension. Total FN and FN-EDA isoform expression increased in response to Ad5.TGFβ2. These data suggest that both TLR4 and FN-EDA contribute to TGFβ2 induced ocular hypertension.

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“…Associations between refractive error and genes involved in ECM growth and remodeling have been reported in individual gene studies, and in genome-wide association studies (25,26,58–64). In the eye, BMPs have been shown to inhibit excessive TGF-β2 induction of ECM proteins (65–69). Since we have shown that absence of Lrp2 leads to modulation of genes influenced by Bmp overexpression, we hypothesized that Lrp2 may assist in fine-tuning Bmp levels to properly control deposition and turnover of ECM proteins.…”

Section: Resultsmentioning

confidence: 99%

Proteolytic processing of LRP2 on RPE cells regulates BMP activity to control eye size and refractive error

Collery

Link

2018

Preprint

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Mutations in LRP2, a transmembrane receptor, cause ocular enlargement and high-myopia. LRP2 is expressed by the RPE and eye ciliary epithelia, binding many extracellular ligands, including Bmp4 and Shh. Signaling mediated by LRP2 is very context-dependent, and how multiple pathways are coordinated is unknown. Transcriptome analyses of ocular tissues revealed that controlled, sustained BMP signaling from the RPE is critical for normal eye growth and emmetropia (proper refraction). Using zebrafish, we demonstrate that BACE sheddase-dependent LRP2 cleavage produces a soluble domain that binds BMP4, inhibiting its signaling. We propose that controlled proteolytic cleavage of LRP2 makes two ligand-binding receptor forms available: a soluble BMP trap, and a membrane-bound RPE signaling facilitator. By modulating LRP2 cleavage, cells can fine-tune and coordinate multiple signaling pathways, as well as growth and turnover of the extracellular matrix, control of which is important to maintain proper eye size. This data supports the concept that LRP2 acts as a homeostasis node that buffers and integrates diverse signaling to regulate emmetropic eye growth.Author SummaryFor proper focusing and normal vision, the axial length of the eye needs to match the refractive power of the lens. This is achieved by fine-tuning multiple signaling pathways to regulate the shape of the eye primarily by remodeling of the sclera, the outermost layer of the eye. This process is termed emmetropization. Emmetropization cues are initiated by visual input, but how signals are transduced from the photoreceptors across the retinal pigment epithelium to the sclera is incompletely understood. Here we show that cleavage of Lrp2, a large receptor expressed on RPE cells in the eye, alters BMP signaling, which contributes to proper eye size control. Dysregulation of BMP signaling by a) absence of Lrp2 in mutant zebrafish or b) overexpression of BMP antagonists from the RPE both cause eye enlargement and myopia. Understanding how regulated cleavage of Lrp2 affects paracrine signaling provides critical insight to emmetropization, raising the possibility for development of therapeutic agents to combat the epidemic incidence of refractive error.

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BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

Cited by 31 publications

References 72 publications

WITHDRAWN: The extract of a Traditional Chinese Medicine alleviates Hepatic Fibrosis of Rats by inhibiting NF-κB activation and upregulating BAMBI in Hepatic Stellate Cells

WITHDRAWN: The extract of a Traditional Chinese Medicine alleviates Hepatic Fibrosis of Rats by inhibiting NF-κB activation and upregulating BAMBI in Hepatic Stellate Cells

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling

Proteolytic processing of LRP2 on RPE cells regulates BMP activity to control eye size and refractive error

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