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Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice.

Tijdschriftbijdrage - Tijdschriftartikel

OBJECTIVE: We earlier identified that the histone methyltransferase Disruptor of telomeric silencing 1-like (DOT1L) is as a master protector of cartilage health via limiting excessive activation of the Wnt pathway. However, cartilage-specific homozygous Dot1l knockout mice exhibited a severe growth phenotype and perinatal death, which hampered their use in induced or ageing models of osteoarthritis (OA). The aim of this study was to generate and examine haploinsufficient and inducible conditional Dot1l-deficient mouse models to evaluate the importance of DOT1L during post-traumatic or ageing-associated OA onset and progression. METHOD: We used cartilage-specific heterozygous and postnatal tamoxifen-inducible Dot1l knockout mice and performed destabilization of the medial meniscus (DMM) and ageing as OA models. Mice were examined histologically using X-rays and micro-computed tomography (μCT), and cartilage damage and osteophyte formation were assessed based on OARSI guidelines. Immunohistochemistry of DOT1L, H3K79me2, TCF1 and COLX was performed. RESULTS: Both Dot1l-deficient strains exhibit a phenotype characterized by joint remodeling with extensive osteophyte formation and ectopic ossification upon ageing, indicating accelerated development of spontaneous osteoarthritis. In the DMM-induced OA mouse model, absence of Dot1l resulted in increased cartilage damage. Wnt signalling hyper-activation and ectopic chondrocyte hypertrophy were observed in the articular cartilage of both Dot1l-deficient mice. CONCLUSIONS: This study demonstrated the functional relevance of DOT1L in vivo during the development of OA using genetically modified mice. Thus, maintaining or enhancing DOT1L activity during ageing or after trauma might prevent OA onset and progression.
Tijdschrift: Osteoarthritis Cartilage
Issue: 3
Volume: 27
Pagina's: 513 - 525
Jaar van publicatie:2019