Background A Genome-Wide Association Study (GWAS) in hand OA has identified the association of hypomorphic variants within ALDH1A2 and severe hand OA (Styrkarsdottir U, et al. 2014). This gene encodes the enzyme catalysing the production of all-trans retinoic acid (atRA). atRA has an essential role in embryonic limb development, but its role in adult cartilage and in OA remains unclear. Previous work from our lab has shown that cartilage injury activates inflammatory signalling and regulates the expression of inflammatory genes.
Trapeziectomy is a surgical treatment for patients with intractable base of thumb OA and is a good source of hand OA cartilage.
Objectives The aim of this study was to investigate the expression of atRA-dependent and inflammatory genes in the cartilage of patients and to examine these with respect to the presence/absence of polymorphic ALDH1A2 variants. We also investigate the regulation of atRA upon cartilage injury and its effect on injury-induced inflammatory gene regulation.
Methods We collected 26 trapeziectomy samples, and dissected the cartilage within one hour of collection. Genomic DNA was extracted for the identification of the two common variants (SNP rs4238326 and SNP rs3204689). Expression levels of atRA-dependent and inflammatory genes were tested by RT-PCR.
Healthy cartilage was obtained from femoral heads of 5-week-old mice and porcine metacarpophalangeal joints of 3–6 months old pigs. Gene regulation upon cartilage injury was tested. To examine the role of specific injury-induced pathways, porcine joints were pre-injected with selective inhibitors to: TGFβR, FGF2R, TAK1 and CYP26, 1 hour prior to injury.
Results Polymorphic variants in ALDH1A2 were common in this patient population and we identified 8 patients homozygous for both variants, and 5 patients who were wild type for both variants. mRNA levels of ALDH1A2 and atRA-dependent gene CYP19A were significantly lower in the homozygous group compared to wild type (figure 1). There were also trends in the regulation of several other atRA-dependent genes. Conversely, inflammatory genes such as HAS1, TSG6 and ADAMTS5 showed a general increase in homozygous patients.
Cartilage injury in both porcine and murine tissue led to a rapid down-regulation of atRA-dependent genes (CYP26s and RARs). Injecting joints with a potent TAK1 inhibitor prevented the drop of atRA-dependent genes. Prior injection of the joint with a CYP26 (enzymes that normally break down atRA) inhibitor, restored levels of atRA-dependent genes after injury and suppressed injury-induced inflammation genes.
Conclusions Polymorphic variants in ALDH1A2 are associated with significantly lower levels of ALDH1A2 and CYP19A1 mRNA in hand OA cartilage. Adult articular cartilage constitutively produces atRA, and this is strongly suppressed by mechanical injury through TAK1 activation. Preventing the drop in cellular atRA upon injury, by pre-incubating the joint with a CYP26 inhibitor, restores atRA levels and leads to a reduction in inflammatory gene regulation. These results indicate that atRA plays an important anti-inflammatory role in cartilage and provides a potential novel therapeutic strategy to treat hand OA.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.