Biology subjects

Cornelis, F.

Publications and source records attributed to Cornelis, F..

4 recordsLinked to original sources

bioRxiv2026

SHIP2 deletion in cartilage does not modulate osteoarthritis in a post-traumatic mouse model

ObjectivesThe inositol phosphatase SHIP2 plays a crucial role in skeletal development and chondrocyte differentiation, and mutations in INPPL1 (encoding SHIP2) cause opsismodysplasia, a chondrodysplasia with marked cartilage abnormalities. We investigated whether SHIP2 contributes to structural joint remodeling in osteoarthritis (OA). MethodsA cartilage-specific conditional knockout of SHIP2 was generated using Ship2fl/fl mice crossed with AggrecanCreERT2 mice. OA was induced at 9 weeks of age via destabilization of the medial meniscus (DMM). Sham surgery served as control. Mice were sacrificed 12 weeks post-surgery. Histological evaluation of articular cartilage, synovium, osteophytes, and subchondral bone was performed. Chondrocyte hypertrophy was assessed by type X collagen (COLX) staining, and SHIP1 was evaluated as a potential compensatory mechanism. ResultsDMM surgery induced OA-like changes in all genotypes, including cartilage damage, synovial inflammation, osteophyte formation, and subchondral bone thickening. However, Ship2cCART-KO mice showed no differences in OA-related parameters compared to control littermates. COLX expression increased following DMM surgery, independent of SHIP2 deletion. SHIP1 protein levels were not elevated in SHIP2-deficient mice. ConclusionThese findings indicate that SHIP2, while essential for cartilage development, does not act as a structural disease modifier in post-traumatic OA, suggesting that within this context, SHIP2 is not required for maintaining adult articular cartilage structure and is unlikely to represent a major therapeutic target for modifying structural disease progression.

molecular biology↗

bioRxiv2021

Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis

Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 alpha (HIF-1). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.

cell biology↗

bioRxiv2021

ANP32A represses Wnt signaling across tissues tissues thereby protecting against joint and heart disease

Wnt signaling is key to diverse homeostatic and pathological processes. This cascade is hyper-activated in osteoarthritis, the most common joint disease. Yet, fundamental aspects of Wnt signaling remain undiscovered. Here, we report that ANP32A negatively regulates Wnt signaling across tissues. In cartilage, loss of Anp32a triggered Wnt hyper-activation. Mechanistically, ANP32A directly interacted with Wnt pathway components and inhibited Wnt target genes via histone acetylation masking. Wnt antagonist treatment reduced severity of osteoarthritis in Anp32a-deficient mice preventing osteophyte formation, contrasting with cartilage-protective effects of ANP32A on oxidative stress. Hence, dual therapy targeting Wnt signaling and oxidative stress in Anp32a-deficient mice ameliorated more osteoarthritis features than individual treatments. Anp32a loss also resulted in Wnt hyper-activation in the heart with cardiac hypertrophy, and in the hippocampus, shedding light on mechanisms for reported links between ANP32A and Alzheimers disease. Collectively, this work reveals that ANP32A is a translationally relevant repressor of Wnt signaling, impacting homeostasis and disease across tissues.

cell biology↗

bioRxiv2018

A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N=30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 73 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 24 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value [≤] 0.019 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N=110). Only one SNV in SUPT20H, c.73T>A (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.\n\nAuthor summaryRheumatoid arthritis (RA) is one of the most frequent auto-immune disease in the world. It causes joint swellings and pains which can lead to mobility impairment. To date, the scientific community has identified a hundred genes carrying variants predisposing to RA, in addition to the major gene HLA-DRB1. However, they do not explain all cases of RA. By examining nine families with multiple RA cases, we identified a new rare nonsense variant in SUPT20H gene, c.73T>A (p.Lys25*). This finding is supported by the literature as the SUPT20H gene regulates several biological functions, such as macro-autophagy or monocyte/macrophage differentiation, that contribute to RA pathogenesis.

genomics↗