Epigenetics during osteoarthritis

Project leader : Jérôme Lafont

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

Although many epigenetic modifications have been described during osteoarthritis (OA), the precise contribution of the chromatin remodeling enzymes during OA is still unclear. The histone demethylase LSD-1 (Lysine-Specific-Demethylase-1) is up-regulated in OA joints and induces the expression of inflammatory molecules such as mPges-1. We found that LSD1 downregulates the COL9A1 gene, which encodes a structural protein of the cartilage collagen fibrils (the type IX collagen) synthesised by articular chondrocytes. These results suggest that LSD1 plays an important role in articular cartilage, notably as a potential promoter of OA. Thus we study the LSD-1 mediated epigenetic signaling in the context of cartilage homeostasis and test the inhibition of LSD-1 as a strategy to prevent OA.

We use Tamoxifen-inducible conditional knockout (cKO) mice to invalidate Lsd-1 specially in chondrocytes (Col2a1-CreERT: lsd-1fl/fl) to evaluate the impact of the absence of Lsd-1 on OA development. Various technics (IHC, FISH qPCR etc…) are used to characterise the joints and to evaluate the OA progression in post-traumatic OA (surgically-induced). The mechanisms (epigenetic signaling) by which catabolic/anabolic genes are regulated by LSD-1 are also investigated through in vitro approaches.

Left: structural analysis of LSD-1 (PyMol) highlights the potential site for protein-protein interactions (histone and non-histone). Right: safranin-o staining of knee joint section of sham vs. surgically-induced OA mice (DMM).

Selected publications : 

1. Lafont JE, Moustaghfir S, Durand AL, Mallein-Gerin F. The epigenetic players and the chromatin marks involved in the articular cartilage during osteoarthritis. Front Physiol. 2023 Jan 17;14:1070241. doi: 10.3389/fphys.2023.1070241. eCollection 2023. PMID: 36733912

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

7. 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