Differential response to intracellular stress in the skin from osteogenesis imperfecta Brtl mice with lethal and non lethal phenotype: A proteomic approach

Bianchi, Laura; Gagliardi, Assunta; Gioia, Roberta; Besio, Roberta; Tani, Chiara; Landi, Claudia; Cipriano, Maria Augusta; Gimigliano, Anna; Rossi, Antonio; Marini, Joan C.; Forlino, Antonella; Bini, Luca

doi:10.1016/j.jprot.2012.01.038

Cited by 19 publications

(42 citation statements)

References 63 publications

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“…We show here that type I collagen expression is significantly upregulated in both mouse models of OI (together with Bglap and Sparc ), suggesting perhaps a futile attempt to increase bone formation. ER stress responses to misfolded procollagen chains can contribute to the pathogenesis of OI mouse models . Therefore, upregulation of type I collagen expression in osteocytes suggests that these cells also experience the negative long‐term consequences of ER stress due to misfolded procollagen chains.…”

Section: Discussionmentioning

confidence: 99%

“…ER stress responses to misfolded procollagen chains can contribute to the pathogenesis of OI mouse models. (53,54) Therefore, upregulation of type I collagen expression in osteocytes suggests that these cells also experience the negative long-term consequences of ER stress due to misfolded procollagen chains. We did not detect differential expression of factors that mediate the unfolded protein response (UPR), which may suggest an unconventional cell stress response similar to what was described in osteoblasts from the G610C (Amish) mouse model of OI.…”

Section: Discussionmentioning

confidence: 99%

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The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta

et al. 2019

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Osteocytes are long‐lived, highly interconnected, terminally differentiated osteoblasts that reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions including in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of abnormal bone matrix is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from Crtap KO and oim/oim mouse models of osteogenesis imperfecta (OI) compared with wild‐type (WT) control mice. To do this, RNA was extracted from osteocyte‐enriched cortical femurs and tibias, sequenced and subsequently analyzed to identify differentially expressed transcripts. These models were chosen because they mimic two types of OI with different genetic mutations that result in distinct type I collagen defects. A large number of transcripts were dysregulated in either model of OI, but 281 of them were similarly up‐ or downregulated in both compared with WT controls. Conversely, very few transcripts were differentially expressed between the Crtap KO and oim/oim mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF‐β but also highlighted new candidate genes to pursue in future studies. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI with potential long‐term consequences at the cellular level, which deserve further investigations. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta

et al. 2019

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“…A priori, stimulating remodeling activity may not be efficacious in the context of the abnormal matrix production and cellular dysfunction that may be caused by qualitative collagen defects. For example, a reported increase in unfolded protein response in a murine model of OI may worsen in situations where osteoblastic function is stimulated (23,24). In fact, in the patients with more severe OI, there was a blunted increase in serum P1NP and an exaggerated increase in urine NTx, and changes in BMD were not different than those observed with placebo, which suggests that teriparatide may have a less favorable effect in more severe disease.…”

Section: Figurementioning

confidence: 95%

Evaluation of teriparatide treatment in adults with osteogenesis imperfecta

Orwoll¹,

Shapiro²,

Veith³

et al. 2014

J. Clin. Invest.

160

101

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Background. Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.Methods. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dualenergy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.Results. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.Conclusions. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength.Trial registration. Clinicaltrials.gov NCT00131469.

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“…The last component of the complex, CyPB, is an ER peptidyl-proyil cis - trans isomerase (PPIase), from the immunophilin family [17] , that is responsible for the cis - trans isomerization of peptidyl-prolyl bonds, a rate-limiting step for collagen folding [18] . CyPB also acts as a member of many foldase and chaperone complexes, including BIP, GRP94, PDI, calreticulin, and calnexin, some of which we previously found deregulated in the Brtl −/+ knock-in murine model of dominant OI [19] .…”

Section: Introductionmentioning

confidence: 90%

Cytoskeleton and nuclear lamina affection in recessive osteogenesis imperfecta: A functional proteomics perspective

Gagliardi

Besio

Carnemolla

et al. 2017

Journal of Proteomics

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Osteogenesis imperfecta (OI) is a collagen-related disorder associated to dominant, recessive or X-linked transmission, mainly caused by mutations in type I collagen genes or in genes involved in type I collagen metabolism.Among the recessive forms, OI types VII, VIII, and IX are due to mutations in CRTAP, P3H1, and PPIB genes, respectively. They code for the three components of the endoplasmic reticulum complex that catalyzes 3-hydroxylation of type I collagen α1Pro986. Under-hydroxylation of this residue leads to collagen structural abnormalities and results in moderate to lethal OI phenotype, despite the exact molecular mechanisms are still not completely clear.To shed light on these recessive forms, primary fibroblasts from OI patients with mutations in CRTAP (n = 3), P3H1 (n = 3), PPIB (n = 1) genes and from controls (n = 4) were investigated by a functional proteomic approach. Cytoskeleton and nucleoskeleton asset, protein fate, and metabolism were delineated as mainly affected. While western blot experiments confirmed altered expression of lamin A/C and cofilin-1, immunofluorescence analysis using antibody against lamin A/C and phalloidin showed an aberrant organization of nucleus and cytoskeleton.This is the first report describing an altered organization of intracellular structural proteins in recessive OI and pointing them as possible novel target for OI treatment.SignificanceOI is a prototype for skeletal dysplasias. It is a highly heterogeneous collagen-related disorder with dominant, recessive and X-linked transmission. There is no definitive cure for this disease, thus a better understanding of the molecular basis of its pathophysiology is expected to contribute in identifying potential targets to develop new treatments.Based on this concept, we performed a functional proteomic study to delineate affected molecular pathways in primary fibroblasts from recessive OI patients, carrying mutations in CRTAP (OI type VII), P3H1 (OI type VIII), and PPIB (OI type IX) genes. Our analyses demonstrated the occurrence of an altered cytoskeleton and, for the first time in OI, of nuclear lamina organization. Hence, cytoskeleton and nucleoskeleton components may be considered as novel drug targets for clinical management of the disease.Finally, according to our analyses, OI emerged to share similar deregulated pathways and molecular aberrances, as previously described, with other rare disorders caused by different genetic defects.Those aberrances may provide common pharmacological targets to support classical clinical approach in treating different diseases.

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Differential response to intracellular stress in the skin from osteogenesis imperfecta Brtl mice with lethal and non lethal phenotype: A proteomic approach

Cited by 19 publications

References 63 publications

The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta

The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta

Evaluation of teriparatide treatment in adults with osteogenesis imperfecta

Cytoskeleton and nuclear lamina affection in recessive osteogenesis imperfecta: A functional proteomics perspective

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