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Osteoarthritis-Associated Variants in Retinoic Acid Synthesis Gene Point to Potential Treatment

NEW YORK — Gene variants that affect retinoic acid synthesis may also be involved in the cartilage damage and inflammation seen in osteoarthritis, a new study has found. The analysis also suggests that drugs blocking retinoic acid metabolism could represent a potential osteoarthritis treatment.

A previous genome-wide association study linked common polymorphic variants in ALDH1A2 to severe osteoarthritis of the hands. ALDH1A2 encodes an enzyme needed for the synthesis of all-trans retinoic acid (atRA), a derivative of vitamin A that is used in a number of skin and acne medications.

In a new study, researchers from the University of Oxford confirmed this association between ALDH1A2 and osteoarthritis and further examined how these variants may affect the disease process. As they reported Wednesday in Science Translational Medicine, they found a reciprocal relationship between ALDH1A2 and inflammatory gene expression. In addition, an experimental acne treatment could suppress the inflammatory genes in animal models of osteoarthritis, suggesting it could treat the condition.

"Hand osteoarthritis is a common and debilitating medical condition that affects mainly women, especially around the time of the menopause," senior author Tonia Vincent, a professor of musculoskeletal biology at Oxford, said in a statement. "We currently have no effective treatments that modify their disease."

The study was funded by Versus Arthritis, a UK charity.

The Oxford-led team first confirmed that the two SNPs at the ALDH1A2 locus that were associated with osteoarthritis in an Icelandic population were also associated with hand osteoarthritis within the UK Biobank study population. Following that, they collected trapezia samples — a bone at the base of the thumb joint — from 33 patients undergoing trapezium removal surgery due to osteoarthritis of the hand.

Patients, they found, had a high prevalence of the ALDH1A2 risk alleles. Further, through RNA sequencing, they also found individuals who were homozygous or heterozygous for the risk alleles had lower levels of ALDH1A2 mRNA in linked cartilage tissue samples than those without the risk alleles.

By stratifying 19 patients by whether they were homozygous for the high- or low-risk variants, the researchers examined differences in gene expression by genotype. Fifteen genes differed in expression and were enriched for involvement in inflammatory pathways. They further uncovered thousands of genes that showed co-variation with ALDH1A2 gene expression, noting that the expression of ALDH1A2 was linked to the reduced expression of inflammatory genes and pathways.

The researchers also noted that a number of genes they linked to ALDH1A2 were known to be regulated by cartilage mechanical injury — which itself has a key role in the development of osteoarthritis. For instance, in both porcine and murine models of cartilage injury, atRA-inducible genes were downregulated while inflammatory genes were upregulated.

This suggested that an atRA metabolism blocking agent (RAMBA) like talarozole (TLZ), an experimental acne treatment that works by inhibiting CYP26, could raise atRA levels and prevent mechano-inflammation.

When porcine joints were injected with TLZ prior to injury, the researchers noted that levels of atRA-inducible genes, such as CYP26A1 and CYP26B1, did not fall, while a number of inflammatory genes were suppressed. They additionally found that TLZ's ability to suppress mechano-inflammation was mediated by a mechanism dependent on peroxisome proliferator-activated receptor gamma.

Further, in mice, systemic treatment with TLZ could suppress mechano-inflammatory genes for six hours after injury and reduce cartilage degradation and osteophyte formation after 26 days.

"Together with the observation that TLZ is able to suppress disease severity in mice after induction of [osteoarthritis], these data identify a potential disease-modifying class of drugs for use in human disease," first author Linyi Zhu, a researcher at the University of Oxford, and colleagues wrote in their paper.

A small proof-of-concept clinical study is underway, according to Oxford.

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