RESEARCH PAPER
Gene modulation in buccal epithelial cells of patients with fibrodysplasia ossificans progressiva treated with ascorbic acid and propranolol.
1
Faculty of Medicine - FAMED, Federal University of Mato Grosso do Sul – UFMS, Brazil
2
Department of Physiology and Biophysics, ICB - UFMG, Brazil
3
Department of Molecular Biology, Institute for Assistance in Research, Education and Health – IAPES,MS, Brazil
4
Health and Education, Instituto de Assistência em Pesquisa, Educação e Saúde – Iapes, Brazil
5
Graduate Program of Physiology and Pharmacology-ICB, Federal University of Minas Gerais - UFMG, Brazil
6
Department of Physiotherapy, UCDB/ Dom Bosco Catholic University. CG,MS, – Brazil
7
National Institute of Science and Technology (INCT) in nano biopharmaceuticals-Department of Physiology and Biophysics, ICB - UFMG, Brazil
8
Department of Pediatrics , Institute for Assistance in Research, Education and Health – IAPES, MS, Brazil
Corresponding author
KEYWORDS
heterotopic ossificationascorbic acidpropranololfibrodysplasia ossificans progressivamouth epithelial cellsFOP inflammation
TOPICS
ABSTRACT
Introduction and objective:
Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disease which at birth may present hallux brevis and valgus as pathognomonic signs. Post-natal heterotopic ossification (HO) progresses into disabling, inflammatory flare-ups. Mutated ACVR1 gene (e.g.: c.617G>A) dysregulates the bone morphogenic protein (BMP) signaling pathway, alters SMAD and p38 MAPK phosphorylation downstream cascades, while Activin-A, through ACVR1 (R206H), signals BMP through Smad1/5 and the TGF-β pathways, activating Smad2/3 canonical cascades, converging to a fate of RUNX2 activation into HO. Expansion of therapeutic possibilities aim to other inflammation pathways. The reninangiotensin system (RAS) is a putative candidate. Its inflammatory axis may converge along FOP canonic ones. Yet, FOP biological specimen collection for molecular studies is an obstacle due to the risk of flare-up. The aim of the study is to evaluate RAS receptors, ass well as potential inflammatory and osteogenic target genes.
Material and methods:
Buccal epithelial cell scrapings (BEC) were collected from healthy controls, untreated FOP patients and 90 days AA+PP treated patients. BEC total RNA was obtained for RT-qPCR gene expression analysis.
Results:
Increased expressions in basal TNFα and ADRβ2, plus tendency of RUNX2, genes in BEC of untreated FOP patients compared with healthy control volunteers were confirmed. AT1R, AT2R, MAS1 and MRGD genes appeared undifferentiated in BEC FOP at baseline, while AA+PP downregulated these four RAS receptor (RASr) genes to levels below controls and normalized TNFα, ADRβ2 and RUNX2.
Conclusions:
The results imply that AA+PP can modulate genes in FOP BEC non-canonical physiopathology pathways related to inflammation, cell signaling and osteogenesis processes.
Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disease which at birth may present hallux brevis and valgus as pathognomonic signs. Post-natal heterotopic ossification (HO) progresses into disabling, inflammatory flare-ups. Mutated ACVR1 gene (e.g.: c.617G>A) dysregulates the bone morphogenic protein (BMP) signaling pathway, alters SMAD and p38 MAPK phosphorylation downstream cascades, while Activin-A, through ACVR1 (R206H), signals BMP through Smad1/5 and the TGF-β pathways, activating Smad2/3 canonical cascades, converging to a fate of RUNX2 activation into HO. Expansion of therapeutic possibilities aim to other inflammation pathways. The reninangiotensin system (RAS) is a putative candidate. Its inflammatory axis may converge along FOP canonic ones. Yet, FOP biological specimen collection for molecular studies is an obstacle due to the risk of flare-up. The aim of the study is to evaluate RAS receptors, ass well as potential inflammatory and osteogenic target genes.
Material and methods:
Buccal epithelial cell scrapings (BEC) were collected from healthy controls, untreated FOP patients and 90 days AA+PP treated patients. BEC total RNA was obtained for RT-qPCR gene expression analysis.
Results:
Increased expressions in basal TNFα and ADRβ2, plus tendency of RUNX2, genes in BEC of untreated FOP patients compared with healthy control volunteers were confirmed. AT1R, AT2R, MAS1 and MRGD genes appeared undifferentiated in BEC FOP at baseline, while AA+PP downregulated these four RAS receptor (RASr) genes to levels below controls and normalized TNFα, ADRβ2 and RUNX2.
Conclusions:
The results imply that AA+PP can modulate genes in FOP BEC non-canonical physiopathology pathways related to inflammation, cell signaling and osteogenesis processes.
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| eISSN: | 1898-7516 |
| ISSN: | 1898-2395 |
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