Author Archives: Jerome Lafont

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Internship M2: role of α10β1integrin in chondrocyte mechanotransduction

Equipe: Biologie et ingénierie du cartilage

Contact: emeline.groult@ibcp.fr

Date: année universitaire 2019-2020

Although osteoarthritis (OA) can be initiated by multiple factors at multiple sites, mechanical overloading remains a key feature of OA pathogenesis. OA may result from excessively aberrant or physiologically normal mechanical stresses on initially healthy or pathologically-impaired articular
cartilage, bone and ligaments. There is thus a need to decipher the mechanotransduction pathways involved in these tissues since alterations in these pathways likely increase the risk of OA. Our project focuses on the mechanotransduction in cartilage. Chondrocytes exposed to mechanical
forces transmit the signals via various mechanotransducers including stretch-activated ion channels, receptor tyrosine kinases, the hyaluronan receptor CD44 and integrins. Integrins are transmembrane proteins consisting of a and β subunits and almost all cartilage proteins bind to integrins.
Chondrocytes primarily use β1 integrins for adhesion to the cartilage matrix but the participation of the individual β1 integrin heterodimers in articular cartilage mechanotransduction is not clearly defined. While most literature data propose the fibronectin receptor a5β1 integrin as a critical
mechanotransducer, the role of the prominent collagen-binding integrins such as a10β1 is unknown. The prominent expression of a10β1 integrin in articular chondrocytes and the partially overlapping chondrodysplasia phenotype of Itga10 null mice and mice with cartilage-specific deletion of Itgb1 makes us think that a10β1 is an integrin heterodimer which plays pivotal roles for functional and mechanical integrity of the joint tissue.

Internship project: Our specific objective is to determine the role of α10β1 in chondrocytes mechanotransduction. We will use a cell system consisting of wild-type or Itga10 null chondrocytes embedded within agarose hydrogels and submitted to compression. We will investigate the impact of a10 privation on the phosphorylation state of signaling molecules and transcriptome. This project will bring new insight into how chondrocytes respond to mechanical forces, under the control of a10β1 integrin.


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Internship M2: Investigating the role of LSD1 in the regulation of the Extracellular Matrix production by the chondrocytes and its consequences during osteoarthritis

Equipe: Biologie et ingénierie du cartilage

Contact: jerome.lafont@ibcp.fr

Date: année universitaire 2019-2020

Articular cartilage is an avascular tissue with limited regenerative capacity. During osteoarthritis (OA), a multifactorial degenerative joint disease, the articular surface becomes eroded, due to the progressive loss of the extracellular matrix. Preventing this degradation or restoring the cartilage matrix is challenging because the molecular mechanisms regulating the matrix gene expression are unclear. Increasing evidence indicates that the gene expression is controlled by epigenetic mechanisms that may be involved during OA. In the chondrocytes, recent studies have identified several histone modifiers acting as transcriptional co-regulator of key regulators of cartilage formation and chondrocyte differentiation.

In the lab, we work on the Lysine-specific histone demethylase 1 (LSD1), an histone demethylase up-regulated in OA and involved in mediating the inflammatory effects of Il-1β. Our results show that LSD1 could be an important regulator of cartilage biology since it affects one cartilage-specific collagen the COL9A1 in vitro. We also observed that LSD1 is in complex with SOX9, a crucial transcription factor involved in the regulation of several matrix genes of the cartilage (submitted article). We think it may be a new co-regulator of SOX9 with potential important consequences for pathologies of cartilage such as OA. We thus intend to investigate the role of LSD1 in vivo through KO mice.

In the project, new target genes of LSD1 (identified following RNA-Seq) will be confirmed using various technics of cell culture, biochemical and molecular biology. We intend to describe how LSD1 affects the SOX9-regulated genes. The work will be first based on human primary chondrocytes cultured in their specific environment (hypoxia etc…), in which the LSD1 gene will be depleted or overexpressed, then the in vivo role of LSD1 during OA will be studied using a mouse model of OA. Our lab has the expertise in all aspects of cartilage biology and developed appropriate collaborations. We look for a highly motivated student interested in cell and molecular biology and aiming at applying for a PhD.

Contact: jerome.lafont@ibcp.fr