Repression Of Wolf-Hischhorn Syndrome Candidate-1 (WHSC1) Contributes To The Osteoarthritis-Inducing Cartilage Loss Of Functions

Francisco Espinoza¹, Yves-Marie Pers², Paul Chuchana³, Jean Marc Brondello⁴ and Christian Jorgensen², ¹INSERM U844, MONTPELLIER, France, ²Department of therapy & Immuno-Rhumatology, Inserm U844, CHU saint-Eloi, Université Montpellier 1, CHU Lapeyronie, Montpellier, France, ³INSERM U844, Montpellier, France, ⁴Inserm U844, UM1, Montpellier, France

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: cartilage, epigenetics and osteoarthritis, Senescent Cells

Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Accumulation of senescent p16^INK4A-positive cells within numerous tissues through out life span contributes to the onset of several age-related disease such as intervertebral disc degenerescence or osteoarthritis (OA). These cells are believed to induce tissue degenerescence and age-dependent loss of functions through the establishment of one senescence-associated secretory phenotype (SASP) including pro-inflammatory cytokines (e.g IL-6, IL-8) and hypertrophic-associated matrix degrading enzymes (e.g MMP1/13 and ADAMTS5). Understanding the molecular mechanism in particular epigenetic regulators leading to the establishment of such deleterious secretome, is a next challenge. Here, we investigate the role and the regulation of the histone H3K36Me2 methyltranferase, WHSC1 (NSD2/MMSET) in cartilage loss of functions in OA.

Methods: We used primary human OA chondrocytes, specific siRNA interference, western-blot, transient transfection, IL-1b treatment, RT-qPCR, Elisa and statistical analysis.

Results: We found that WHSC1 mRNA expression is reduced in OA senescent-like cartilage compared to healthy donors. WHSC1 mRNA and protein levels are as well reduced in human primary chondrocytes following IL-1b chronic treatment. By a loss of function experiment based on specific siRNA against WHSC1, we found an up-regulation of MMP1, MMP13 and ADAMTS5 mRNA accumulation but not pro-inflammatory cytokines (IL-8, IL-6) in primary chondrocytes. As result, WHSC1-depleted chondrocytes show a reduced expression in Aggrecan and a slight increase production in GAG.

Conclusion:

Our preliminary data demonstrate that WHSC1 impacts articular homeostasis maintenance by repressing part of the senescence-associated secretome induced in OA. Further experiments are required in particular for understanding how WHSC1-dependent epigenetic regulation of these hypertrophic-associated matrix-remodeling factors, occurs.

Disclosure:

F. Espinoza,
None;

Y. M. Pers,
None;

P. Chuchana,
None;

J. M. Brondello,
None;

C. Jorgensen,
None.

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