Dataset Information

Understanding the Action of RAR? Agonists on Human Osteochondroma Explants.

ABSTRACT: Osteochondromas are cartilage-capped growths located proximate to the physis that can cause skeletal deformities, pain, limited motion, and neurovascular impingement. Previous studies have demonstrated retinoic acid receptor gamma (RAR?) agonists to inhibit ectopic endochondral ossification, therefore we hypothesize that RAR? agonists can target on established osteochondromas. The purpose of this study was to examine the action of RAR? agonist in human osteochondromas. Osteochondroma specimens were obtained during surgery, subjected to explant culture and were treated with RAR? agonists or vehicles. Gene expression analysis confirmed the up-regulation of RAR? target genes in the explants treated with NRX 204647 and Palovarotene and revealed strong inhibition of cartilage matrix and increased extracellular matrix proteases gene expression. In addition, immunohistochemical staining for the neoepitope of protease-cleaved aggrecan indicated that RAR? agonist treatment stimulated cartilage matrix degradation. Interestingly, cell survival studies demonstrated that RAR? agonist treatment stimulated cell death. Moreover, RNA sequencing analysis indicates changes in multiple molecular pathways due to RAR? agonists treatment, showing similarly to human growth plate chondrocytes. Together, these findings suggest that RAR? agonist may exert anti-tumor function on osteochondromas by inhibiting matrix synthesis, promoting cartilage matrix degradation and stimulating cell death.

SUBMITTER: Garcia SA

PROVIDER: S-EPMC7215996 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Understanding the Action of RARγ Agonists on Human Osteochondroma Explants.

Garcia Sonia A SA Tian Hongying H Imamura-Kawasawa Yuka Y Fisher Aidan A Cellini Ashley A Codd Casey C Herzenberg John E JE Abzug Joshua M JM Ng Vincent V Iwamoto Masahiro M Enomoto-Iwamoto Motomi M

International journal of molecular sciences 20200413 8

Osteochondromas are cartilage-capped growths located proximate to the physis that can cause skeletal deformities, pain, limited motion, and neurovascular impingement. Previous studies have demonstrated retinoic acid receptor gamma (RARγ) agonists to inhibit ectopic endochondral ossification, therefore we hypothesize that RARγ agonists can target on established osteochondromas. The purpose of this study was to examine the action of RARγ agonist in human osteochondromas. Osteochondroma specimens w ...[more]

PMID: 32294904

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Project description:Study hypothesisMyometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition.Study findingGene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset.What is known alreadyCirculating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model.Study design, samples/materials, methodsMyometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants.Main results and the role of chanceGene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 µM P4 led to a reduction in interleukin-1 (IL-1) β-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset.Limitations/reasons for cautionThere is evidence of basal inflammation in the myometrial explant model.Wider implications of the findingsMyometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour.Large scale dataData deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830.Study funding and competing interestThis work was supported by grants from the Joint Research Committee of the Westminster Medical School Research Trust, Borne (No. 1067412-7; a sub-charity of the Chelsea and Westminster Health Charity) and the Imperial NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS or the Department of Health. The authors have no conflict of interest.

Dataset Information

Understanding the Action of RAR? Agonists on Human Osteochondroma Explants.

Publications

Understanding the Action of RARγ Agonists on Human Osteochondroma Explants.

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