The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction

Abstract

Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation.Methods. OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage.Results. The first-year tESR and the OPG: RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio.Conclusion. This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).

Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis

“…Radiographic progression was weakly associated with the RANKL level but was not at all associated with the OPG level. A stronger association between radiographic progression and the OPG-to-RANKL ratio was observed (17). Unfortunately, we were unable to measure serum RANKL in the present study, due to the lack of availability of a sufficiently reliable assay.…”

“…This may emphasize the importance of analyzing OPG levels in the context of serum RANKL, the primary ligand for binding to RANK on the cell surface, resulting in osteoclast activation. This point is highlighted in the findings of a study of these 2 biomarkers as predictors of radiographic progression in RA (17). Radiographic progression was weakly associated with the RANKL level but was not at all associated with the OPG level.…”

“…Examples include serum cartilage oligomeric matrix protein (COMP) (13), human cartilage gp-39 (YKL-40) (14), which reflects cartilage remodeling and synovial hyperplasia, and serum matrix metalloproteinase 3 (MMP-3) (15,16), which primarily reflects synovial inflammation. Other categories of biomarkers shown to independently predict joint damage in patients with RA include cytokines that regulate the process of osteoclast activation, such as RANKL and soluble osteoprotegerin (OPG) (17).…”

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

“…Prior to this discovery, conclusions regarding the possible impact of elevated total RANKL levels in rats were tempered by the lack of corresponding information on OPG levels. The RANKL to OPG ratio is considered an important determinant of bone resorption in arthritis [68]. The new ability to quantify OPG and RANKL in rats is an important advance due to the widespread use of rats as models for investigating human bone disease.…”

Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint

“…Examples are osteoprotegerin (OPG), RANKL, and matrix metalloproteinase 3 (MMP-3), which are all primarily markers that reflect joint tissue remodeling. The baseline OPG:RANKL ratio was observed to be an independent predictor of the level of joint destruction later in the disease course (7). Such an association is reported for baseline MMP-3 levels as well, although its association was dependent on a correlation with traditional risk factors such as anti-CCP antibodies (8).…”