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Abstract
RANKL is a type II transmembrane protein cytokine of the TNF-superfamily and is a key player in bone metabolism. It plays a critical role in the regulation of osteoclastogenesis and regulation of osteogenic disorders such as osteoporosis and JRA. Two isoforms are produced by alternate splicing, a membrane-anchored protein (mRANKL) and a secreted soluble molecule (sRANKL). Although both forms are bioactive, the mRANKL seems to be the homeostatic form, while the production of sRANKL signals pathological condition.
RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the main regulator of osteoclastogenesis, and was found to be the primary culprit responsible for the enhanced activation and differentiation of osteoclasts in the presence of M-CSF. RANKL is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells.
The aim of this study was to explore the role of RANKL in the development of bone erosions and osteoporosis in children with JRA. Also, to demonstrate the expression of serum soluble RANKL (sRANKL) in relation to the clinical, laboratory, and radiological variables of JRA disease activity, severity and progression. This may pave way for targeting RANKL as a novel approach to JRA.
This case-control study comprised 50 patients suffering from JRA (15 of whom were newly diagnosed). A control group comprised 20 healthy age and sex-matched children with the studied patients and another of 15 children with non-erosive arthritis due to systemic lupus erythematosus (SLE) included for the purpose of comparison of laboratory data.
At enrollment, all children with JRA were subjected to detailed clinical assessment, radiological evaluation of the joints (plain radiography), measurement of bone mineral density (BMD) using DEXA (Dual Energy X-ray Absorptiometry), and measurement of serum soluble RANKL using enzyme linked immunoassay. To assess the relation of RANKL expression to disease progression and to investigate whether baseline soluble RANKL levels can predict the development of bone erosions and osteoporosis, a group of newly diagnosed JRA children (n =15) was subjected to serum soluble RANKL assay, plain radiography, and BMD measurement twice: initially at recruitment for the first time then 2 years later.
Serum sRANKL levels of all JRA patients during disease activity ranged between 0.07 and 3.71 pmol/l (median = 2.81, mean ± SD = 2.19 ± 3.03 pmol/l). These values were significantly higher when compared to the values of healthy children which ranged from 0.01 to 0.87 pmol/l (median = 0.31, mean ± SD = 0.23 ± 0.04 pmol/l, Z = 2.5; P < 0.0001). Serum sRANKL levels of SLE children during activity ranged between 0.03 and 1 pmol/l (median = 0.46, mean SD = 0.17 0.13 pmol/l). These values were statistically comparable to the values of controls, but were significantly lower than the values of JRA children. The baseline serum levels of sRANKL of the 15 newly diagnosed JRA children were statistically comparable when compared to the corresponding values assayed 2 years later.
The highest serum sRANKL level was found in children with polyarticular onset JRA. The levels were significantly higher in children presented with extra-articular manifestations and those with long-term JRA. Moreover, serum levels could be related to the duration of illness.
At recruitment, serum sRANKL levels could be related to the variables of disease activity and severity namely; summed joint index score, ESR, RF titers, ANA seropositivity, total Larsen score, and the presence of bone erosions.
During follow up of the 15 newly diagnosed children, seven children developed erosive disease at the end of 2 years. Their serum sRANKL levels were significantly higher in comparison to those without erosive disease. Moreover, the baseline of serum levels of sRANKL in children who developed erosive disease correlated positively with the corresponding values at the end of 2 years.
Decreased BMD in the osteopenic and osteoporotic range was found in 52% and 18% respectively. BMD Z scores in all JRA children ranged between -3.11 to 2.63 (mean ± SD = -0.13 ± 1.19). The mean ± SD BMD (gm/cm2) at the lumbar spines (L2-L4), the neck of the femur, and the radius were 0.72 ± 0.12, 0.88 ± 0.19 and 0.48 ± 0.16 g/cm2 respectively. The baseline mean ± SD BMD of the 15 newly diagnosed JRA children were statistically comparable when compared to the corresponding values assayed 2 years later. BMD Z scores were inversely associated with the duration illness, high Larsen score, and RF titers. Children with BMD Z score of -1.5 or lower had significantly higher serum sRANKL levels than patients with BMD Z score higher than -1.5. A significant negative correlation was found between the serum sRANKL levels and BMD.
In conclusion, RANKL was up regulated in children with JRA. The up regulation is more evident in polyarticular onset JRA and could be related to disease severity, disease progression, and joint destruction. Serum sRANKL levels can predict clinical and radiological outcome occurring years later. The up regulation of RANKL seems to serve in enhanced osteoclastogenesis and activation of the bone resorptive function, both of which might play important roles in bone and cartilage destruction. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the BMD Z scores as evident by DEXA. These data suggest that early diagnosis could reduce the likelihood of reduced BMD in these patients by prompting intervention strategies at an early stage.
Measurement of serum sRANKL although not a diagnostic marker for JRA, yet can be considered a very informative serological marker in terms of disease severity, and disease progression reflecting the underlying bone degrading activity. Further studies, are warranted to evaluate the role of sRANKL in complex immune interactions and in the etiopathogenesis of JRA i.e. beyond its well-known spectrum on osteoclastogenesis. Elucidation of other mechanisms mediating osteoclast differentiation and function are warranted. RANKL blockade (using OPG or RANK fusion proteins or human RANKL antibodies [denosumab]) should be addressed thoroughly in terms of efficacy and safety in children with aggressive JRA.