The signaling pathways under the control of hypoxia, a physiological condition of normal cartilage

Project leader : J. Lafont

Participants  : F. Mallein-Gerin, M. Pasdeloup, Sherine Moustaghfir


The articular 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 location where cartilage still lies (such as articular cartilage) will stay avascular, and will play a mechanical protection of long bone. Thus the resident cells of adult cartilage live and are influenced by a complex microenvironment characterised by its 3D structure, mechanical forces and a hypoxic gradient.

Observation of embedded chondrocytes from human explant of articular cartilage (optical microscopy).

The microenvironment, such as hypoxia, regulates the expression of chondrocyte markers.

During cartilage formation, chondrocytes are in a hypoxic environment, which induces expression of the survival factor VEGF. Beyond this effect, hypoxia stimulates the expression of matrix genes specific to cartilage (encoding the two main proteins of cartilage, aggrecan and type II collagen). We demonstrated, using human articular chondrocytes (primary culture), that 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 hypoxic conditions, we have shown that HIF-2alpha (Hypoxia-Inducible Factor) stimulates the expression of SOX9 and modulates a set of genes associated with the chondrocyte phenotype.

The effects of the surrounding hypoxia on the biology of chondrocytes is of high interest to understand the cartilage disease such as OA, but also in cartilage engineering stargtegies. We study the underlying mechanisms of such an hypoxic regulation, notably through the epigenetic signaling, in order to decipher the pathogenesis of OA, and to propose molecular tools allowing a better control of the chondrocyte function.

A.                               B.
Observation of human articular cartilage from healthy and osteoarthritic joints. Neovascularisation appears in the OA cartilage whereas the absence of vessels is specific of the healthy cartilage (A). Mouse model is used to identify epigenetic signaling potentially involved in the pathogenesis of OA. Knee joint was labelled with anti-COL II antibody (B).

Selected publications : 

1. Durand AL, Dufour A, Aubert-Foucher E, Oger-Desfeux C, Pasdeloup M, Lustig S, Servien E, Vaz G, Perrier-Groult E, Mallein-Gerin F, Lafont JE (2020). The Lysine Specific Demethylase-1 Negatively Regulates the COL9A1 Gene in Human Articular Chondrocytes.  Int J Mol Sci. 2020 Aug 31;21(17):6322. doi: 10.3390/ijms21176322. PMID: 32878268.

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

3. 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.

4. 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 articular 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. M. Cohen Solal, Bioscar Laboratory (U1132), Hopital Lariboisière, Paris

Pr. S. Lustig and E. Servien, Hôpital de la Croix-rousse, Lyon

Dr. R. Debret, équipe fonctionnalité et dynamique du tissu cutané (UMR 5305-LBTI)