DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Silvia Monteagudo, Frederique M. F. Cornelis, Carolina Aznar-Lopez, Ploi Yibmantasiri, Laura-An Guns, Peter Carmeliet, Frédéric Cailotto and Rik J. Lories ()
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Silvia Monteagudo: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Frederique M. F. Cornelis: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Carolina Aznar-Lopez: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Ploi Yibmantasiri: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Laura-An Guns: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Peter Carmeliet: Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven
Frédéric Cailotto: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
Rik J. Lories: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15889

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