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Accueil du site > Equipes > Biologie et Ingénierie du Cartilage (F. Mallein-Gerin) > Thématiques > Voies de signalisation sous contrôle de l’hypoxie, condition physiologique du cartilage > Voies de signalisation sous contrôle de l’hypoxie, condition physiologique du cartilage

Voies de signalisation sous contrôle de l’hypoxie, condition physiologique du cartilage

Project leader : J. Lafont

People involved in the project : F. Mallein-Gerin, A-L. Durand, M. Pasdeloup


The chondrocytes are normally under chronic hypoxia.
During development, cartilage is a transient tissue precluding the skeletal bone. Remplacement of primary cartilage by bone is possible after vascularisation which allows osteoblast precursors invasion. However, some specific locations where cartilage still lies (such as articular cartilage) will stay avascular. Thus resident cells of adult cartilage survive in a low oxygen environment (hypoxic gradient) compared to atmosphere. This cartilage is an interface between several tissues and plays a mechanical protection of long bone. Its homeostasis is regulated through the diffusion of soluble factors released by surrounding tissues (subchondral bone, synovial fluid).

Hypoxia regulates the expression of chondocyte markers.
During cartilage formation, chondrocytes are in a hypoxic environment, which induces expression of VEGF, a survival factor for the cells. Beyond its effets, hypoxia stimulates the expression of matrix genes specific to cartilage (coding the two main proteins of cartilage, aggrecan and type II collagen). We demonstrate using human articular chondrocytes (primary culture), hypoxia increases the expression of chondrocyte markers among which the transcription factor Sox9. This transcription factor is part of a transcriptionnal machinery that controls the expression of col2a1 and aggrecan genes. Under hypoxia environment, HIF-2alpha (Hypoxia-Inducible Factor) stimulates the expression of Sox9 and modulates a set of genes associated with the chondrocyte phenotype.

The chondrocytes are thus adapted to hypoxic life, and their normal physiology depends on these conditions. The effects of hypoxia on the biology of chondrocytes is of high interest in cartilage enginering as it could help improving therapies of cartilage based on culture of primary chondrocytes. We study the underlying mechanisms of such a hypoxic regulation (signaling, epigenetics) in order to identify new targets and to propose molecular tools, allowing better control of the function of chondrocyte.

From Lafont J. (2010), Int. Journal of Exp. Pathol. (91)2:99-106


Selected publications

1. Lafont JE, Poujade FA, Pasdeloup M, Neyret P, Mallein-Gerin F. Hypoxia potentiates the BMP-2 driven COL2A1 stimulation in human articular chondrocytes via p38 MAPK. Osteoarthritis Cartilage. 2016 May ;24(5):856-67. doi : 10.1016/j.joca.2015.11.017.

2. Thoms BL, Dudek KA, Lafont JE and Murphy CL (2013). Hypoxia promotes production and inhibits destruction of human articular cartilage. Arthritis and Rheum. 2013 May 65(5)1302-12. doi : 10.1002/art.37867.

3. Dudek KA§, Lafont JE§, Martinez-Sanchez A, Murphy CL. (2010). Type II collagen expression is regulated by tissue-specific MIR-675 in human articular chondrocytes. The Journal of Biol. Chem. 285 (32) : 24381-7. doi : 10.1074/jbc.M110.111328.

4. Murphy CL, BL Thoms, RJ Vaghjiani and JE Lafont (2009). HIF-mediated chondrocyte function : prospects for cartilage repair. Arth. Res. and Ther. 11(1):213

5. Lafont JE, Talma S, Hopfgarten C, Murphy CL (2008). Hypoxia promotes the differentiated human articular chondrocyte phenotype through Sox9-dependent and independent pathways. The Journal of Biol. Chem. 283 (8) 4778-4786



Collaborations

Pr. P. Neyret and E. Servien, hôpital de la croix Rousse, (HCL trust)

Dr R. Debret, Team "function and dynamics of cutaneous tissue" UMR 5305-LBTI