Journal Article

DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Guns, Laura-An, Monteagudo, Silvia, Cailotto, Frédéric, Lories, Rik J., Cornelis, Frederique M. F., Yibmantasiri, Ploi, Aznar-Lopez, Carolina, Carmeliet, Peter

2017

Overview

Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis. DOT1L is one of the few genes linked to osteoarthritis by human GWAS. Here the authors show that DOT1L-dependent histone methylation protects homeostasis of articular chondrocytes by SIRT1-dependent inhibition of canonical WNT signalling, and that inhibition of DOT1L can drive osteoarthritic disease in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 13/89 / 13/95 / 14 / 38 / 38/61 / 631/208/176 / 631/80/304 / 692/4023/1670/407 / 82 / 96 / Animals / Arthritis / Benzimidazoles - pharmacology / Benzimidazoles - toxicity / Biochemistry, Molecular Biology / Biocompatibility / Biomedical materials / Cartilage / Cartilage - metabolism / Cartilage - pathology / Cartilage diseases / Cells, Cultured / Cellular Biology / Chondrocytes / Chondrocytes - drug effects / Chondrocytes - metabolism / Female / Gene Expression Regulation / Homeostasis / Human health and pathology / Humanities and Social Sciences / In vitro methods and tests / Life Sciences / Male / Methylation / Methyltransferases - genetics / Methyltransferases - metabolism / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Osteoarthritis / Osteoarthritis - chemically induced / Osteoarthritis - metabolism / Osteoarthritis - pathology / Rhumatology and musculoskeletal system / Science / Science (multidisciplinary) / Signal transduction / Signaling / SIRT1 protein / Sirtuin 1 - genetics / Sirtuin 1 - metabolism / Transcription / Wnt protein / Wnt Signaling Pathway