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Étude de la régulation transcriptionnelle du gène Indian Hedgehog et de son rôle dans l'ostéoarthrose
| Content Provider | Semantic Scholar |
|---|---|
| Author | Bernard, Lauriane |
| Copyright Year | 2011 |
| Abstract | Introduction: Osteoarthritis (OA) is the most common joint disorder and is characterized by cartilage degradation and endochondral ossification. One in every ten Canadians is affected, yet its aetiopathogenesis remains unknown. In this present study, two new regulators of the IHH promoter, NFAT1 and PITX1, were studied. The downregulation of IHH expression by these factors could contribute to the OA pathogenesis. The Hedgehog (Hh) signaling pathway regulates chondrocyte growth and differentiation in the growth plate. Indian hedgehog (IHH), one of its members, stimulates chondrocyte proliferation and osteoblast differentiation. IHH is essential in skeletogenesis, osteoblastogenesis and cartilage growth. Method and Results: A 5 kbp fragment of the Ihh murin promoter was cloned upstream to the luciferase reporter gene in the pGL3 vector. By in silico analysis, several consensus conserved sites of NFAT1 and PITX1 were identified on the Ihh promoter. Cotransfections with NFAT1, a growth and differentiation cellular repressor in cartilage, show an inhibition of the Ihh promoter activity in osteoblasts and an activation in chondrocytes. The same experiments with PITX1, a transcriptional factor involved in the development of himb limbs and the maintenance of the cartilaginous function, show a significant activation of the IHH promoter activity in chondrocytes. Using an RNAi approach against these factors led to results that are consistent with the over-expression assays. Chromatin immunoprecipitation assay (ChIP) was performed to confirm the presence of NFAT1 in the IHH promoter. The OA articular cartilage shows high levels of prehypertrophic chondrocytes. RT-qPCR reveals a repression of the Hh pathway as well as an inhibition of the expression of NFAT1 and PITX1 in OA patients, when compared to non-affected controls. Conclusion: This project allowed to shed light on two new transcriptional regulators of the IHH gene activity promoter, NFAT1 and PITX1. These two regulators activate IHH in chondrocytes and NFAT1 also inhibits its expression in osteoblasts. Furthermore, a deficiency of these two genes in OA patients coincide with a decrease of the expression of genes implicated in the Hedgehog signaling pathway. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://papyrus.bib.umontreal.ca/xmlui/bitstream/handle/1866/8305/Bernard_Lauriane_2011_memoire.pdf;jsessionid=AF04B5ED5643A7F153FAEB2EB810792F?sequence=2 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
