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Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

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Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica. / Chan, Wing Lee; Steiner, Magdalena; Witkos, Tomasz; Egerer, Johannes; Busse, Björn; Mizumoto, Shuji; Pestka, Jan M; Zhang, Haikuo; Hausser, Ingrid; Khayal, Layal Abo; Ott, Claus-Eric; Kolanczyk, Mateusz; Willie, Bettina; Schinke, Thorsten; Paganini, Chiara; Rossi, Antonio; Sugahara, Kazuyuki; Amling, Michael; Knaus, Petra; Chan, Danny; Lowe, Martin; Mundlos, Stefan; Kornak, Uwe.

In: PLOS GENET, Vol. 14, No. 3, 21.03.2018, p. e1007242.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Chan, WL, Steiner, M, Witkos, T, Egerer, J, Busse, B, Mizumoto, S, Pestka, JM, Zhang, H, Hausser, I, Khayal, LA, Ott, C-E, Kolanczyk, M, Willie, B, Schinke, T, Paganini, C, Rossi, A, Sugahara, K, Amling, M, Knaus, P, Chan, D, Lowe, M, Mundlos, S & Kornak, U 2018, 'Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica', PLOS GENET, vol. 14, no. 3, pp. e1007242. https://doi.org/10.1371/journal.pgen.1007242

APA

Chan, W. L., Steiner, M., Witkos, T., Egerer, J., Busse, B., Mizumoto, S., Pestka, J. M., Zhang, H., Hausser, I., Khayal, L. A., Ott, C-E., Kolanczyk, M., Willie, B., Schinke, T., Paganini, C., Rossi, A., Sugahara, K., Amling, M., Knaus, P., ... Kornak, U. (2018). Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica. PLOS GENET, 14(3), e1007242. https://doi.org/10.1371/journal.pgen.1007242

Vancouver

Chan WL, Steiner M, Witkos T, Egerer J, Busse B, Mizumoto S et al. Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica. PLOS GENET. 2018 Mar 21;14(3):e1007242. https://doi.org/10.1371/journal.pgen.1007242

Bibtex

@article{d47c87db055a4092a35a75a5b1c4234d,
title = "Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica",
abstract = "Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.",
keywords = "Journal Article",
author = "Chan, {Wing Lee} and Magdalena Steiner and Tomasz Witkos and Johannes Egerer and Bj{\"o}rn Busse and Shuji Mizumoto and Pestka, {Jan M} and Haikuo Zhang and Ingrid Hausser and Khayal, {Layal Abo} and Claus-Eric Ott and Mateusz Kolanczyk and Bettina Willie and Thorsten Schinke and Chiara Paganini and Antonio Rossi and Kazuyuki Sugahara and Michael Amling and Petra Knaus and Danny Chan and Martin Lowe and Stefan Mundlos and Uwe Kornak",
year = "2018",
month = mar,
day = "21",
doi = "10.1371/journal.pgen.1007242",
language = "English",
volume = "14",
pages = "e1007242",
journal = "PLOS GENET",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "3",

}

RIS

TY - JOUR

T1 - Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

AU - Chan, Wing Lee

AU - Steiner, Magdalena

AU - Witkos, Tomasz

AU - Egerer, Johannes

AU - Busse, Björn

AU - Mizumoto, Shuji

AU - Pestka, Jan M

AU - Zhang, Haikuo

AU - Hausser, Ingrid

AU - Khayal, Layal Abo

AU - Ott, Claus-Eric

AU - Kolanczyk, Mateusz

AU - Willie, Bettina

AU - Schinke, Thorsten

AU - Paganini, Chiara

AU - Rossi, Antonio

AU - Sugahara, Kazuyuki

AU - Amling, Michael

AU - Knaus, Petra

AU - Chan, Danny

AU - Lowe, Martin

AU - Mundlos, Stefan

AU - Kornak, Uwe

PY - 2018/3/21

Y1 - 2018/3/21

N2 - Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

AB - Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

KW - Journal Article

U2 - 10.1371/journal.pgen.1007242

DO - 10.1371/journal.pgen.1007242

M3 - SCORING: Journal article

C2 - 29561836

VL - 14

SP - e1007242

JO - PLOS GENET

JF - PLOS GENET

SN - 1553-7404

IS - 3

ER -