Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

International audienceOsteoarthritis (OA) is characterized by cartilage degradation, inflammation, and hypertrophy. Therapies are mainly symptomatic and aim to manage pain. Consequently, medical community is waiting for new treatments able to reduce OA process. This study aims to develop an in vitro simple OA model useful to predict drug ability to reduce cartilage hypertrophy. Human primary OA chondrocytes were incubated with transforming growth factor beta 1 (TGF-β1). Hypertrophy was evaluated by Runx2, type X collagen, MMP13, and VEGF expression. Cartilage anabolism was investigated by Sox9, aggrecan, type II collagen, and glycosaminoglycan expression. In chondrocytes, TGF-β1 increased expression of hypertrophic genes and activated canonical WNT pathway, while it decreased dramatically cartilage anabolism, suggesting that this treatment could mimic some OA features in vitro. Additionally, EZH2 inhibition, that has been previously reported to decrease cartilage hypertrophy and reduce OA development in vivo, attenuated COL10A1 and MMP13 upregulation and SOX9 downregulation induced by TGF-β1 treatment. Similarly, pterosin B (an inhibitor of Sik3), and DMOG (a hypoxia-inducible factor prolyl hydroxylase which mimicks hypoxia), repressed the expression of hypertrophy markers in TGF-β stimulated chondrocytes. In conclusion, we established an innovative OA model in vitro. This cheap and simple model will be useful to quickly screen new drugs with potential anti-arthritic effects, in complementary to current inflammatory models, and should permit to accelerate development of efficient treatments against OA able to reduce cartilage hypertrophy

A case of Hajdu-Cheney syndrome associated with psoriatic rheumatism, two causes of acro-osteolysis

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Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature

International audienceThe role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in COMP (Cartilage Oligomeric Matrix Protein) associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis. By screening potential causal genes for osteoarthritis, we identified a heterozygous missense mutation of COMP (c.1358C>T, p.Asn453Ser), absent from genome databases, located on a highly conserved residue and predicted to be deleterious. Molecular dynamics simulation suggests that the mutation destabilizes the overall COMP protein structure and consequently the calcium releases from neighboring calcium binding sites. This mutation was once reported in the literature as causal for severe multiple epiphyseal dysplasia (MED). However, no sign of dysplasia was present in the index case. The mutation was also identified in one of her brothers diagnosed with MED and secondary osteoarthritis, and in her sister affected by an atypical syndrome including peripheral inflammatory arthritis of unknown cause, without osteoarthritis nor dysplasia. This article suggests that this mutation of COMP is not only causal for idiopathic early-onset osteoarthritis or severe MED, but can also be associated to a broad phenotypic variability with always joint alterations

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis

International audienceHistone methyltransferase EZH2 is upregulated during osteoarthritis (OA), which is the most widespread rheumatic disease worldwide, and a leading cause of disability. This study aimed to assess the impact of EZH2 inhibition on cartilage degradation, inflammation and functional disability. In vitro, gain and loss of EZH2 function were performed in human articular OA chondrocytes stimulated with IL-1β. In vivo, the effects of EZH2 inhibition were investigated on medial meniscectomy (MMX) OA mouse model. The tissue alterations were assayed by histology and the functional disabilities of the mice by actimetry and running wheel. In vitro, EZH2 overexpression exacerbated the action of IL-1β in chondrocytes increasing the expression of genes involved in inflammation, pain (NO, PGE2, IL6, NGF) and catabolism (MMPs), whereas EZH2 inhibition by a pharmacological inhibitor, EPZ-6438, reduced IL-1β effects. Ex vivo, EZH2 inhibition decreased IL-1β-induced degradation of cartilage. In vivo, intra-articular injections of the EZH2 inhibitor reduced cartilage degradation and improved motor functions of OA mice. This study demonstrates that the pharmacological inhibition of the histone methyl-transferase EZH2 slows the progression of osteoarthritis and improves motor functions in an experimental OA model, suggesting that EZH2 could be an effective target for the treatment of OA by reducing catabolism, inflammation and pain. Abbreviations DNZep 3-Deazanoplanocin A EZH2 Enhancer of Zest Homolog 2 GFP Green Fluorescent Protein H3K27 Lysine 27 of the histone 3 IL-1β Interleukin-1β IL-6 Interleukin 6 JMJD3 Jumonji Domain Containing 3 MMP Matrix metalloproteinase MMX Medial meniscectomy NGF Nerve Growth Factor NO Nitric oxide OA Osteoarthritis PGE2 Prostaglandin E2 Osteoarthritis (OA) is the most widespread rheumatic disease worldwide, and one of the main causes of pain and disability, reducing patient's quality of life 1. OA affects 1 in 3 people over age 65 and women more than men 2. In the United States, 22.7% of the adult population (52.5 million of persons) report having been diagnosed with OA by their physician. The impact on healthcare expenses is massive. The cost of knee OA alone is, for instance