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Fibroblasts in soft tissue mineralization display an osteogenic gene expression pattern but do not transform into mature osteoblasts

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Abstract
AIM: soft tissue mineralization (STM) can occur in a single tissue or generalized, leading to important morbidity and mortality e.g. in renal, brain and eye disease. Mechanistically, vascular STM is best characterized with osteogenic differentiation of smooth muscle cells (SMC) losing their SMC identity as a driving mechanism. The paradigm disorder for generalized STM is pseudoxanthoma elasticum (PXE), where calcification of elastic fibers leads to skin, ocular, cardio- and cerebrovascular symptoms. The fibroblast is considered a leading cell type but the underlying mechanisms are poorly understood. We investigated whether fibroblasts in tissue-wide STM can differentiate into osteoblasts, driving mineral deposition. METHODS and RESULTS: we evaluated the mediators coordinating osteoblast differentiation by immunohistochemistry and mRNA expression profiling in skin tissue and fibroblasts of PXE patients, and eyes and whiskers of the PXE murine model. We show upregulation of BMP2, TGFβ2 and downstream Smads, promoting pre-osteoblast formation, and the key regulators of osteoblast differentiation, RUNX2 and β-catenin. The acquired osteoblast gene expression profile was further evidenced by cellular ALPL stains and increased ERAP2-Wnt osteogenic signaling on expression array. However, fibroblasts do not transdifferentiate into mature osteoblasts as main transcription factors for the latter, e.g. osterix, remain normal. CONCLUSION: STM in PXE results from osteogenic differentiation of fibroblasts, driven by BMP2-SMADs-RUNX2, TGFβ2-SMAD and ERAP2-Wnt signaling. Contrary to osteogenic differentiation of SMCs, no complete transdifferentiation to mature osteoblasts with loss of cellular identity occurs. This suggests reversibility with the potential for therapeutic intervention.

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MLA
Van Gils, Matthias et al. “Fibroblasts in Soft Tissue Mineralization Display an Osteogenic Gene Expression Pattern but Do Not Transform into Mature Osteoblasts.” Research Day Faculty of Medicine and Health Sciences, Abstracts. 2016. Print.
APA
Van Gils, M., De Vilder, E., Hosen, M., Coucke, P., LeSaux, O., De Paepe, A., & Vanakker, O. (2016). Fibroblasts in soft tissue mineralization display an osteogenic gene expression pattern but do not transform into mature osteoblasts. Research day Faculty of Medicine and Health Sciences, Abstracts. Presented at the Research day Faculty of Medicine and Health Sciences.
Chicago author-date
Van Gils, Matthias, Eva De Vilder, Mohammad Hosen, Paul Coucke, Olivier LeSaux, Anne De Paepe, and Olivier Vanakker. 2016. “Fibroblasts in Soft Tissue Mineralization Display an Osteogenic Gene Expression Pattern but Do Not Transform into Mature Osteoblasts.” In Research Day Faculty of Medicine and Health Sciences, Abstracts.
Chicago author-date (all authors)
Van Gils, Matthias, Eva De Vilder, Mohammad Hosen, Paul Coucke, Olivier LeSaux, Anne De Paepe, and Olivier Vanakker. 2016. “Fibroblasts in Soft Tissue Mineralization Display an Osteogenic Gene Expression Pattern but Do Not Transform into Mature Osteoblasts.” In Research Day Faculty of Medicine and Health Sciences, Abstracts.
Vancouver
1.
Van Gils M, De Vilder E, Hosen M, Coucke P, LeSaux O, De Paepe A, et al. Fibroblasts in soft tissue mineralization display an osteogenic gene expression pattern but do not transform into mature osteoblasts. Research day Faculty of Medicine and Health Sciences, Abstracts. 2016.
IEEE
[1]
M. Van Gils et al., “Fibroblasts in soft tissue mineralization display an osteogenic gene expression pattern but do not transform into mature osteoblasts,” in Research day Faculty of Medicine and Health Sciences, Abstracts, Ghent, Belgium, 2016.
@inproceedings{8610285,
  abstract     = {AIM: soft tissue mineralization (STM) can occur in a single tissue or generalized, leading to important morbidity and mortality e.g. in renal, brain and eye disease. Mechanistically, vascular STM is best characterized with osteogenic differentiation of smooth muscle cells (SMC) losing their SMC identity as a driving mechanism. The paradigm disorder for generalized STM is pseudoxanthoma elasticum (PXE), where calcification of elastic fibers leads to skin, ocular, cardio- and cerebrovascular symptoms. The fibroblast is considered a leading cell type but the underlying mechanisms are poorly understood. We investigated whether fibroblasts in tissue-wide STM can differentiate into osteoblasts, driving mineral deposition. 
METHODS and RESULTS: we evaluated the mediators coordinating osteoblast differentiation by immunohistochemistry and mRNA expression profiling in skin tissue and fibroblasts of PXE patients, and eyes and whiskers of the PXE murine model. We show upregulation of BMP2, TGFβ2 and downstream Smads, promoting pre-osteoblast formation, and the key regulators of osteoblast differentiation, RUNX2 and β-catenin. The acquired osteoblast gene expression profile was further evidenced by cellular ALPL stains and increased ERAP2-Wnt osteogenic signaling on expression array. However, fibroblasts do not transdifferentiate into mature osteoblasts as main transcription factors for the latter, e.g. osterix, remain normal.
CONCLUSION: STM in PXE results from osteogenic differentiation of fibroblasts, driven by BMP2-SMADs-RUNX2, TGFβ2-SMAD and ERAP2-Wnt signaling. Contrary to osteogenic differentiation of SMCs, no complete transdifferentiation to mature osteoblasts with loss of cellular identity occurs. This suggests reversibility with the potential for therapeutic intervention.},
  author       = {Van Gils, Matthias and De Vilder, Eva and Hosen, Mohammad and Coucke, Paul and LeSaux, Olivier and De Paepe, Anne and Vanakker, Olivier},
  booktitle    = {Research day Faculty of Medicine and Health Sciences, Abstracts},
  language     = {eng},
  location     = {Ghent, Belgium},
  title        = {Fibroblasts in soft tissue mineralization display an osteogenic gene expression pattern but do not transform into mature osteoblasts},
  year         = {2016},
}