4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion

Besio, Roberta; Iula, Giusy; Garibaldi, Nadia; Cipolla, Lina; Sabbioneda, Simone; Biggiogera, Marco; Marini, Joan C.; Rossi, Antonio; Forlino, Antonella

doi:10.1016/j.bbadis.2018.02.002

Cited by 65 publications

(94 citation statements)

References 59 publications

(82 reference statements)

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“…Procollagen is degraded mainly in lysosomes but some of collagen mutant chains can be degraded in proteasomes . Interestingly, UPR induction due to retention of mutated collagen type I chains in ER was reported . Therefore, there is an open question whether impairing of collagen secretion may contribute to NEL‐induced ER stress in fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

Szoka

Karna

Andrulewicz-Botulińska

et al. 2019

Experimental Dermatology

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The mechanism for differential effects of human immune deficiency virus protease inhibitors (HIVPIs), nelfinavir (NEL) and indinavir (IND) on collagen metabolism disturbances was studied in human skin fibroblasts. It has been considered that HIVPIs‐dependent deregulation of collagen biosynthesis involves prolidase (an enzyme providing proline for collagen biosynthesis), glutamine (Gln) (a substrate for proline biosynthesis), nuclear factor‐κB (NF‐κB) (a transcription factor that inhibit expression of type I collagen genes), β1 integrin receptor and Akt signalling. It was found that NEL impaired collagen biosynthesis and the process was more pronounced in the presence of Gln, while IND stimulated collagen biosynthesis. NEL‐dependent inhibition of collagen biosynthesis was accompanied by massive intracellular accumulation of type I collagen, while IND slightly induced this process. This effect of NEL was reversed by ascorbic acid but not N‐acetylcysteine. The mechanism for the NEL‐dependent defect in collagen metabolism was found at the level of prolidase activity, β1 integrin signalling and NF‐κB. NEL inhibited expression of β1 integrin receptor, Akt and ERK1/2 and increased expression of p65 NF‐κB. However, inhibitors of p65 NF‐κB did not prevent NEL‐dependent inhibition of collagen biosynthesis suggesting that this transcription factor is not involved in studied mechanism. Using PI3K inhibitor wortmannin that prevent phosphorylation of Akt revealed that NEL‐dependent inhibition of Akt results in inhibition of collagen biosynthesis. The data suggest that differential effect of NEL and IND on collagen metabolism involves NEL‐dependent down‐regulation of Akt signalling and proline availability for collagen biosynthesis.

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Section: Discussionmentioning

confidence: 99%

The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

Szoka

Karna

Andrulewicz-Botulińska

et al. 2019

Experimental Dermatology

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“…For example, with collagen I mutations in OI clear evidence of UPR activation was demonstrated for a procollagen I C‐propeptide trimerization mutation in the Aga2/+ mouse with upregulation of BiP, Hsp47, and Gadd153 (Chop) resulting in osteoblast apoptosis (Lisse et al, ). Recent studies on patient collagen I helix mutations reported upregulation of several components of the UPR, including BiP, PDI, ATF4, phospho‐PERK and XBP1 splicing (Besio et al, ). However, the pattern of upregulation of these individual UPR components was different in the five patient mutations studied.…”

Section: Is Er Stress a Driver Of Pathology With Ecm Protein Structurmentioning

confidence: 99%

“…However, the pattern of upregulation of these individual UPR components was different in the five patient mutations studied. For example, BiP was upregulated in only three of five COL1A1 or COL1A2 mutations tested (Besio et al, ), highlighting that while a UPR can be activated by these mutations, there is apparent mutation specificity in the strength and nature of the response. In a mouse model of mild to moderate OI due to a Col1a2 missense mutation (α2(I) G610C) which disturbs the collagen triple helix, ER accumulation of the mutant misfolded collagen I results in upregulation of CHOP, eiF2α phosphorylation, and chaperones αβ crystalline and HSP47, and it was concluded this ER‐stress did not involve the canonical UPR pathway (Mirigian et al, ).…”

Section: Is Er Stress a Driver Of Pathology With Ecm Protein Structurmentioning

confidence: 99%

“…Improving mutant protein folding by upregulating endogenous chaperones or by administering chemical chaperones that can stabilize proteins in their native conformation and rescue mutant protein folding and/or trafficking defects has been a widely used strategy in protein folding disorders (Perlmutter, ; Ulloa‐Aguirre et al, ; Arakawa et al, ; Rivas et al, ). The FDA‐approved chemical chaperone sodium 4‐phenylbutyrate (PBA) can reduce ER stress in vitro caused by COL1A1 OI mutations (Besio et al, ), COL4A2 (Murray et al, ), and COL4A5 (Wang et al, ) mutations. In a zebrafish model of OI, PBA administration ameliorated the skeletal pathology (Gioia et al, ).…”

Section: Therapeutic Approaches—targeting the Upr?mentioning

confidence: 99%

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Genetic Disorders of the Extracellular Matrix

Lamandé

Bateman

2019

The Anatomical Record

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Mutations in the genes for extracellular matrix (ECM) components cause a wide range of genetic connective tissues disorders throughout the body. The elucidation of mutations and their correlation with pathology has been instrumental in understanding the roles of many ECM components. The pathological consequences of ECM protein mutations depend on its tissue distribution, tissue function, and on the nature of the mutation. The prevalent paradigm for the molecular pathology has been that there are two global mechanisms. First, mutations that reduce the production of ECM proteins impair matrix integrity largely due to quantitative ECM defects. Second, mutations altering protein structure may reduce protein secretion but also introduce dominant negative effects in ECM formation, structure and/or stability. Recent studies show that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, makes a significant contribution to the pathophysiology. This suggests that targeting ER-stress may offer a new therapeutic strategy in a range of ECM disorders caused by protein misfolding mutations. Anat Rec,

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“…TGFbeta [16,17]) and chemical stimulants (e.g. ascorbic acid [17][18][19], glycolic acid [20], 4-phenyl butyric acid (4-PBA) [21] and retinol [22]) to boost the collagen production and matrix deposition. However, these molecules have multiple other roles in the body and the therapies are associated with negative side effects, such as promoting abnormal angiogenesis, or inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

Khan

Sankaran

Llontop

et al. 2019

Preprint

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Background:Collagen is a structural protein that provides mechanical stability and defined architectures to skin. In collagen-based skin disorders like Epidermolysis bullosa, EDS the ability to offer such stability is lost either due to mutations in collagens or defect in the chaperones involved in collagen assembly, which leads to chronic wounds, skin fragility, and blisters. Existing approaches to study and develop therapy against such conditions are the use of small molecules like 4-phenylbutyrate (4-PBA) or growth factors like TGF-β. However, these approaches are not collagen specific resulting in unsolicited responses. Therefore, a collagen specific booster is required to guide the correct folding and deposition of collagen in a highly regulated manner. Hsp47 is a chaperone with a major role in collagen biosynthesis.Expression levels of Hsp47 correlate with collagen production. This article explores the stimulation of collagen deposition by exogenously supplied Hsp47 (collagen specific chaperone) in skin cells, including specific collagen subtypes quantification.Results: Here we quantify the collagen deposition level and the type of deposited collagens by different cell types from skin tissue (fibroblasts NHDF, L929 and MEF, keratinocytes HaCat and endothelial cells HDMEC) after Hsp47 stimulation. We find upregulated deposition of fibrillar collagen subtypes I, III and V after Hsp47 delivery. Network collagen IV deposition was enhanced in HaCat and HDMECs and fibril-associated collagen XII were not affected by the increased Hsp47 intracellular levels. The deposition levels of fibrillar collagen were celldependent i.e. Hsp47-stimulated fibroblasts deposited significantly higher amount of fibrillar collagen than Hsp47-stimulated HaCat and HDMECs. Conclusions:A 3-fold enhancement of collagen deposition was observed in fibroblasts upon repeated dosage of Hsp47 within the first 6 days of culture. Our results provide fundamental understanding towards the idea of using Hsp47 as therapeutic protein to treat collagen disorders. Additional filesAdditional file 1: Figure S1 shows supplementary information on delivery of H47 to ER via KDEL receptor-mediated endocytosis to different cell types.Additional file 2: Figure S2 shows Z-stack orthogonal projection images of NHDF after incubation with EGFP for 3 h.Additional file 3: Figure S3 shows Immunostaining of COL I, III, IV, V and XII deposited in MEF, L929, HaCaT and HDMEC cultures 24 h with and without treatment of H47.Additional file 4: Figure S4 shows Stimulated deposition of COL I, III and V in MEF Hsp47 -/-cells after H47 uptake.Additional file 5: Figure S5 shows H47 binds to collagen on the matrix on L929 cells reaching confluency.

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4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion

Cited by 65 publications

References 59 publications

The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

Genetic Disorders of the Extracellular Matrix

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

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