osteoprotegerin and Arthritis--Juvenile

Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Topics: Animals; Arthritis, Juvenile; Arthritis, Rheumatoid; Bone and Bones; Bone Remodeling; Bone Resorption; Carrier Proteins; Cytokines; Glycoproteins; Humans; Inflammation; Lupus Erythematosus, Systemic; Membrane Glycoproteins; Osteoclasts; Osteogenesis; Osteoprotegerin; Parathyroid Hormone-Related Protein; Prostaglandins; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction; Spondylarthropathies

Children with juvenile idiopathic arthritis (JIA) are at higher risk of decreased bone mineral density (BMD) compared with healthy children due to genetic, disease and medication-related causes. This study aims to investigate the possible effects of osteoprotegerin (OPG) gene polymorphisms and serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor κB-ligand (RANKL) and RANKL/OPG ratio on BMD in children with JIA.. OPG gene rs2073617, rs3134069, serum RANKL, OPG and RANKL/OPG ratio were evaluated in 60 JIA children and 100 matched healthy controls. BMD was evaluated by lumbar dual energy X-ray absorptiometry (DEXA) according to which patients were classified in 2 groups (DEXA z-score above and below - 2). Composite disease activity was measured using the Juvenile Arthritis Disease Activity Score (JADAS) 27-joints. Articular damage was scored using the juvenile arthritis damage index (JADI).. Patients aged 12.05 ± 3.2 years, included 38 females and 31% had BMD z-score below-2. Systemic-onset JIA was the most frequent phenotype (38%). Genotypes and alleles frequencies of the 2 studied polymorphisms did not differ between patients and controls (p > 0.05 for all) while serum RANKL and RANKL/OPG ratio were significantly higher in patients compared to controls (p = < 0.001 and 0.03 respectively). Patients with BMD < -2 had significantly greater frequencies of rs2073617 TT genotype and T allele (p < 0.001), higher serum RANKL, RANKL/OPG ratio (p = 0.01, 0.002), female predominance (p = 0.02), higher articular and extra-articular damage index (p = 0.008,0.009) and more frequent steroid usage (p = 0.02) compared to patients with BMD z-score >-2. Multivariate analysis showed rs2073617 TT genotype, RANKL/OPG ratio, long disease duration (above 36 months) and use of steroid to be associated with decreased BMD (p = 0.03,0.04,0.01,0.01 respectively) in JIA children.. Egyptian children with JIA have decreased BMD. rs2073617 TT genotype and T allele, RANKL/OPG ratio are possible determinants of reduced BMD in JIA. Our results underline the importance of frequent monitoring of BMD in JIA children and trying to control disease activity to preserve long term bone health.

Topics: Arthritis, Juvenile; Bone Density; Child; Egypt; Female; Humans; Male; Osteoprotegerin; Polymorphism, Genetic; RANK Ligand

Juvenile idiopathic arthritis (JIA) is a disease associated with loss of bone mass, deterioration in bone mass quality and an increased risk of fractures. The objective of this study was to evaluate factors that predict bone mineral density (BMD) alterations in young adult patients with active JIA before and during therapy with tumour necrosis factor α (TNFα) inhibitors.. Thirty-one patients (twelve males and nineteen females; mean age =25.1 ± 6.1 years) with active JIA (mean Disease Activity Score in 28 joints (DAS28) =6.36 ± 0.64; mean high-sensitivity C-reactive protein (hsCRP) =18.36 ± 16.95 mg/L) were investigated. The control group consisted of 84 healthy individuals matched by sex and age. BMD, bone turnover markers and serum concentrations of soluble receptor activator of nuclear factor κB ligand, osteoprotegerin, dickkopf Wnt signalling pathway inhibitor 1 (Dkk1) and sclerostin were evaluated.. Baseline BMD values in the lumbar spine, proximal femur, femoral neck and distal radius were significantly lower in patients with JIA compared to healthy control participants. Baseline sclerostin serum concentrations were significantly higher in patients with JIA compared to control participants. After 2 years of treatment with TNFα inhibitors, BMD was significantly increased in the lumbar spine. This increase correlated with a drop in DAS28 score. A statistically significant correlation between hsCRP and Dkk1 was found at baseline, as well as during the 2-year follow-up period. A significant reduction in serum sclerostin after 1 year of therapy was predictive of a drop in DAS28 score observed with a 1-year delay after reduction of serum sclerostin.. A significant correlation between the sclerostin serum concentration and the number of tender and swollen joints, but not BMD, supports the hypothesis that chondrocytes and cells of the subchondral bone may contribute to circulating sclerostin in JIA.

Topics: Absorptiometry, Photon; Adaptor Proteins, Signal Transducing; Adult; Arthritis, Juvenile; Blood Sedimentation; Bone Density; Bone Morphogenetic Proteins; C-Reactive Protein; Female; Femur; Follow-Up Studies; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Lumbar Vertebrae; Male; Osteoprotegerin; Radius; RANK Ligand; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

In chronic arthritis cartilage and bone destruction occur as a consequence of synovial inflammation. It is mainly mediated by matrix metalloproteinases and RANKL-OPG pathways. Data on synovial fluid levels of these mediators in enthesitis related arthritis subtype (ERA) of JIA are not available. MMP-1, MMP-3, TIMP, sRANKL and OPG levels were measured in synovial fluid from patients with ERA and compared with other arthritides, polyarticular (Poly) JIA, RA and osteoarthritis (OA). sRANKL was detectable in 25/41 of ERA patients, 4/16 of Poly JIA patients. Median SF sRANKL level in patients with ERA was higher as compared to OA (p < 0.001) and poly JIA (p < 0.05) but were comparable to RA. The median OPG level in ERA was lower as compared to OA (p < 0.001), comparable to RA but was higher than poly JIA (p < 0.001). sRANKL/OPG ratio was significantly higher in ERA and Poly JIA compared to OA (p < 0.0001, p < 0.0001 respectively). The median MMP3 levels in ERA (74 microg/ml) was lower as compared to poly JIA (410 microg/ml; p < 0.0001) and RA (340 ug/ml; p < 0.0001) but was comparable to OA (107 microg/ml). The median level of ProMMP1 in ERA (0.70 microg/ml) was lower as compared to RA (2.9 microg/ml; p < 0.0001) and poly JIA but was elevated as compared to OA patients (0.1 microg/ml; p < 0.0001). TIMP1 levels in ERA were higher than poly JIA and RA patients. MMP3/TIMP1 ratio was lower in ERA compared to polyarticular JIA patients (p < 0.05). Ours is the first study reporting elevated sRANKL and reduced OPG levels and elevated sRANKL/OPG ratio in SF of children with JIA resulting in a mileu associated with bone loss. In addition, ERA patients had lower MMP level as well as MMP/TIMP ratio as compared to poly JIA which may partly explain lesser degree of joint damage seen in ERA as compared to poly JIA.

Topics: Adolescent; Adult; Aged; Arthritis, Juvenile; Arthritis, Rheumatoid; Child; Child, Preschool; Female; Humans; Male; Matrix Metalloproteinases; Middle Aged; Osteoarthritis; Osteoprotegerin; RANK Ligand; Synovial Fluid; Tissue Inhibitor of Metalloproteinase-1

We studied the serum levels of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), pro-matrix metalloproteinase (MMP) 1, MMP3, and tissue inhibitor of metalloproteinase (TIMP) 1 in patients with juvenile idiopathic arthritis (JIA) and correlated these with different disease variables. Sera of 70 patients with JIA (ILAR 2001 criteria) and 33 age- and sex-matched controls were assayed by enzyme-linked immunosorbent assay. Nonparametric tests were used for analysis of data. The subtype distribution of the JIA patients was: enthesitis-related arthritis (ERA) 24, polyarticular 22, systemic onset 13, oligoarticular 8, and others 3. The median level of RANKL, OPG, pro-MMP1, MMP3, and TIMP-1 were elevated in JIA patients as compared to controls (p < 0.001). There was no difference in levels among different types of JIA. RANKL/OPG ratio was elevated in all subtypes of JIA. MMP3/TIMP-1 ratio correlated with measures of disease activity including swollen and tender joint count, erythrocyte sedimentation rate, and disease activity score (rS 0.28, p < 0.05). Ours is the first study to show elevated RANKL in serum of patients with JIA. Further, our data suggest that patients with ERA have similar levels to other forms of JIA. Association of the MMP3/TIMP-1 ratio with disease activity suggests that it may be a useful biomarker for follow-up.

Topics: Adolescent; Adult; Arthritis, Juvenile; Biomarkers; Case-Control Studies; Child; Child, Preschool; Female; Humans; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Osteoprotegerin; RANK Ligand; Severity of Illness Index; Tissue Inhibitor of Metalloproteinase-1

To evaluate serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor kB-ligand (RANK-L) in patients with juvenile idiopathic arthritis (JIA); to correlate these values with disease activity variables, radiological bone damage, and bone mass; and to correlate OPG gene polymorphisms with bone mass.. Eighty-four patients (66 girls and 18 boys) with JIA and 40 sex and age-matched controls were enrolled. Serum OPG and RANK-L were measured using an enzyme-linked immunosorbent assay. OPG genotyping was performed by polymerase chain reaction.. Patients with JIA had significantly higher levels of serum OPG than controls (p = 0.001) and lower levels of RANK-L in comparison with controls (p = 0.0003). The OPG/RANK-L ratio in patients was higher than in controls (p = 0.004). No significant correlations were found between disease duration, erythrocyte sedimentation rate, and C-reactive protein values with either OPG or RANK-L serum levels. A significant difference in serum OPG levels (but not in RANK-L) was found between patients with and without erosions (p = 0.008). No correlation was found between OPG and RANK-L levels and bone mass (DXA Z scores). A higher prevalence of OPG CC genotype was found in both patients (65.4%) and controls (82.5%) (p = 0.006). Subjects with CC genotype had a higher lumbar spine bone mineral density (LS-BMD).. We evaluated for the first time levels of OPG and RANK-L in children with JIA. The higher OPG/RANK-L ratio in JIA might be the result of a compensatory production of OPG. The presence of the T allele of the OPG gene appears to be associated with low BMD.

Topics: Arthritis, Juvenile; Blood Sedimentation; Bone Density; Bone Resorption; Carrier Proteins; Child; Child, Preschool; DNA; Female; Genetic Predisposition to Disease; Genotype; Glycoproteins; Humans; Joints; Male; Membrane Glycoproteins; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Genetic; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Synovial Fluid; Time Factors

To analyse the expression of receptor activator of NF-kappaB (RANK) and RANK ligand (RANKL) in the joints of children with juvenile idiopathic arthritis (JIA), to characterize the phenotype of RANK(+) cells and to test the hypothesis that some RANK(+) cells are of the dendritic type.. Paired samples of peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from children with oligoarticular (n=14) or polyarticular (n=4) JIA and PBMC from 10 control subjects were studied for expression of RANK, RANKL and dendritic cell-specific ICAM (intercellular adhesion molecule)-grabbing non-integrin (DC-SIGN) by the reverse transcriptase-polymerase chain reaction and three-colour flow cytometry. Expression of DC-SIGN and RANK was followed after 1 week of culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4).. mRNA for RANK was detected in both adherent cells and T cells from PBMC and SFMC of patients with JIA and in control PBMC, while mRNA for RANKL was detectable in the T-cell fraction from JIA patients but not in that from controls. By flow cytometry, a large number of RANK(+) cells were detected in the joint; these cells had the phenotype HLA-DR(hi)CD86(hi) CD11c(+) and expressed low levels of DC-SIGN.. There is increased expression of RANKL and RANK in the juvenile arthritic joint. RANK is expressed on a population of cells with features of dendritic cells. RANK/RANKL interactions may contribute to the survival of inflammatory cells within the joint, as well as to erosions and osteoporosis in juvenile arthritis.

Topics: Adult; Arthritis, Juvenile; Carrier Proteins; Cells, Cultured; Child; Dendritic Cells; Gene Expression; Glycoproteins; Humans; Ligands; Membrane Glycoproteins; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Fluid