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Precise genetics of osteoarthritis

The most common chronic joint disease is osteoarthritis (OA). EU researchers have investigated the role of an epigenetic modifier that plays an important part in the biology and pathology of synovial joints for this disabling disease.
Precise genetics of osteoarthritis
The disruptor of telomeric silencing 1-like (DOT1L) is a transcription control enzyme. As such, it controls many highly dynamic biological processes including DNA damage response, the cell cycle, embryonic development and cell reprogramming.

In the context of OA, earlier research by the DOTOS (DOT1L in osteoarthritis) project found a strong association between variations in the human DOT1L gene and hip cartilage thickness as well as OA. Silencing of DOT1L inhibits chondrogenic differentiation of mouse progenitor cells and the gene is linked with a crucial cascade in cartilage biology.

DOTOS researchers have further elucidated the role of DOT1L by deciphering its transcriptional network in cartilage, investigating its role in joint development and disease. The work was validated by transcriptional analyses from OA patient samples.

Using mass spectrometry, the researchers have identified new DOT1L interacting molecules. By analysis of the microarray data with a range of bioinformatics tools, more members of the DOT1L network were placed according to function.

A complex Dot1l knockout genetic mouse model was bred for the in vivo cartilage formation studies. An in vitro protocol was devised to investigate disease-associated cascades and networks. DOT1L inhibitor was injected intra-articularly into mouse knees to follow the development of spontaneous OA. Research into the role of DOT1L postnatally is ongoing.

DOTOS work on OA development has been submitted to a major high-impact journal. The research results have been presented at prestigious conferences including the European Workshop for Rheumatology Research, which resulted in two awards in consecutive years. The team also won the 2015 Celgene Prize in Rheumatology.

Related information


Osteoarthritis, synovial joints, disruptor of telomeric silencing 1-like, transcription control enzyme, DOTOS, cartilage
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