Is there any role for tumour necrosis factor related apoptosis inducing ligand–osteoprotegerin (TRAIL–OPG) interaction in rheumatoid arthritis?

We read with great interest the article ‘‘Baseline serum RANKL levels may serve to predict remission in patients with rheumatoid arthritis treated with TNF antagonists’’ by Gonzalez-Alvaro, recently published in Annals of Rheumatic Diseases. Other reports have previously shown increased serum levels of RANKL (receptor activator for nuclear factor kB ligand), as well as of osteoprotegerin (OPG), in patients affected by rheumatoid arthritis (RA), and the upregulation of OPG has been usually interpreted as a compensatory mechanism to limit bone erosion due to RANKL activity. In addition, Gonzalez- Alvaro et al stated that low serum levels of baseline RANKL and the RANKL:OPG ratio may be useful to predict remission in patients with established RA receiving anti-tumour necrosis factor (TNF) treatment. Tumour necrosis factor related apoptosis inducing ligand (TRAIL) is an additional TNF family member sharing 25% homology with RANKL. Of note, besides interacting with four high affinity membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4), TRAIL also interacts with OPG with an affinity comparable to RANKL. Interestingly, recent studies have shown that TRAIL is a potent inhibitor of autoimmune arthritis and of osteoclastic maturation. In particular, blocking endogenous TRAIL enhances proliferation of autoreactive lymphocytes or synovial cells with exacerbation of arthritic inflammation and activation of bone reabsorption with joint tissue destruction in RA. On this basis, we have analysed TRAIL and OPG serum levels in 50 patients with RA (36 females and 14 males, mean age 64 years, median disease duration 12 years) and 50 healthy sexmatched controls (35 females and 15 males, all younger than 50 years). In all, 25 patients with RA were treated with steroids plus methotrexate (MTX) and hydroxychloroquine (HCQ), 13 were treated with steroids plus leflunomide and 12 with steroids plus HCQ. TRAIL serum levels were significantly increased in the patients with RA. Additionally, the OPG serum level was significantly higher in patients with RA compared to healthy controls . Similar to the findings of Gonzalez-Alvaro concerning the RANKL:OPG ratio,1 the TRAIL:OPG ratio was not statistically different between the two study groups. Aftermany studies addressing the role of the RANKL:OPG ratio in the determinism of bone destruction in RA and other erosive conditions, our data suggest that the relative levels of expression/ release of TRAIL should be taken into consideration as well. It has been proposed that the OPG increase typical of RA population might have beneficial effects in limiting bone erosion due to RANKL. However, beside the findings demonstrating a role of OPG as inflammatory molecule, whose serum levels are influenced by over expression of cytokines such as TNFa and interleukin (IL)1b,10 we propose that OPG increase in patients with RA may produce detrimental effects by counteracting the anti-arthritogenic and anti-osteoclastic activity of TRAIL. Therefore further studies will be necessary to accurately evaluate the balance among RANKL, TRAIL and OPG in patients with RA and to find out possible correlations between their serum levels and progression/regression of bone damage.