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- Copyright © The Author(s) 2023
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- 10.1186/s42358-023-00294-3
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Abstract
Introduction In chronic arthropathies, there are several mechanisms of joint destruction. In recent years, studies have reported the implication of receptor activator of nuclear factor kappa‑B ligand (RANKL) and osteoprotegerin (OPG) in the process of activation and differentiation of osteoclasts, a key cell in the development of bone erosion. The RANKL/OPG ratio is increased in the serum of patients with malignant diseases and lytic bone disease, as well as rheumatoid arthritis (RA). The objective of this study was to measure and compare the concentrations of OPG and RANKL in the synovial fluid (SF) of patients with rheumatoid arthritis, spondyloarthritis (SpA) and osteoarthritis (OA). Methods This was an observational and cross‑sectional study with 83 patients, 33 with RA, 32 with SpA and 18 with OA, followed up regularly in the outpatient clinics of the Rheumatology Department of the Clinics Hospital of the Ribeirão Preto Medical School‑USP. All patients were assessed for indications for arthrocentesis by the attending physi‑ cians at the time of SF collection and were evaluated for demographic variables and medication use. Disease activity was assessed in individuals with RA and SpA. The quantification of SF OPG and RANKL levels was performed by ELISA, and the correlations of the results with clinical, laboratory and radiological parameters were assessed. Results We found no statistically significant difference in the RANKL and OPG levels among the groups. Patients with RA showed a positive correlation between the SF cell count and RANKL level (r = 0.59; p < 0.05) and the RANKL/ OPG ratio (r = 0.55; p < 0.05). Patients with OA showed a strong correlation between C‑reactive protein (CRP) and the RANKL/OPG ratio (r = 0.82; p < 0.05). There was no correlation between the OPG and RANKL levels and markers of inflammatory activity or the disease activity index in patients with RA or SpA. Conclusion Within this patient cohort, the RANKL/OPG ratio was correlated with the SF cell count in patients with RA and with serum CRP in patients with OA, which may suggest a relationship with active inflammation and more destructive joint disease. Keywords Arthritides, Rheumatoid arthritis, Spondyloarthropathy, Osteoarthrosis, OPGL protein, RANKL protein *Correspondence: Renê Donizeti Ribeiro de Oliveira rdroliveira@hcrp.usp.br Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Quaresma et al. Advances in Rheumatology (2023) 63:13 Page 2 of 8 disease activity indices (in RA and SpA) and the presence Introduction of subchondral cysts (OA) and bone erosions. Chronic arthropathies are a heterogeneous set of diseases characterized by a broad range of synovial inflammation. Methods Among the main chronic arthropathies are immune- Study design and patients mediated arthropathies, such as rheumatoid arthritis This was a cross-sectional study involving a convenience (RA) and the spondyloarthritis (SpA) disease spectrum, sampling of patients with rheumatic disease undergoing and primary osteoarthritis (OA), the best example of a arthrocentesis (diagnostic or therapeutic), from whom primarily degenerative arthropathy [1]. All of these can synovial fluid was obtained from May 2020 to April 2022, lead to joint dysfunction, with different degrees of mor - at the Rheumatology Outpatient Clinic of the Hospital of bidity [2]. Although they have different clinical manifes - the Clinics of the School of Medicine of Ribeirão Preto of tations, these diseases share events in the pathogenesis the University of São Paulo (HCRP-USP). of joint injury, such as cartilage destruction, subchondral The inclusion criteria for the sample were a medi - cysts formation and bone erosion [3–5]. In RA and SpA, cal indication for arthrocentesis and joint aspiration; bone erosion is directly related to the progression of joint age over 18 years; and understanding and signing of the dysfunction [6, 7]. OA is associated with loss of articu- informed consent form. Patients with RA were classified lar cartilage and joint tissue destruction along with bone according to the American College of Rheumatology/ remodeling (mostly sclerosis and osteophytes) resulting European League Against Rheumatism (ACR/EULAR) in altered joint function and pain. Subchondral cysts are criteria [20]. Patients with SpA met the criteria of the common in long-term disease, but joint erosions are not Assessment of SpondyloArthritis international Society a characteristic and seen in only a small subset of patients (ASAS) group [21], and those with OA met the crite- [8]. ria of the OsteoArthritis Research Society International Among the important cellular events related to osteo- (OARSI) [22]. chondral erosion is osteoclast activation. Synovial and The exclusion criteria were as follows: other chronic cell surface markers of osteoclasts, both of which have a inflammatory diseases that could interfere with the pro-erosive effect, are found in the synovium and bone inflammatory response, such as other rheumatic dis - erosion sites in chronic arthropathies [9, 10]. Receptor eases, acute or chronic infectious diseases (including sep- activator of nuclear factor kappa-B activator receptor tic arthritis), and neoplasia under treatment or for which ligand (RANKL) and osteoprotegerin (OPG) are essential treatment had been completed less than 5 years prior. in the recruitment and action of these cells [11]. RANKL One hundred ninety-one patients were evaluated for is a surface molecule, a potent stimulator of bone resorp- eligibility. For each of them, the SF was obtained from tion involved in the differentiation and activation of one knee. Nineteen patients had a presumptive diagno- osteoclasts. OPG is produced and released by activated sis of chronic inflammatory arthropathy without meet - osteoblasts and inhibits osteoclast maturation and activa- ing any of the classification criteria, which led to their tion. The relationship between RANKL and OPG levels is noninclusion. Eighty-nine patients were excluded for the an indirect measure of osteoclastogenesis at the site eval- following reasons: septic arthritis (43 cases); microcrys- uated [11]. The RANKL/OPG ratio is high in the serum talline arthritis (27 cases), other rheumatic diseases (12 of patients with malignant diseases and tumor bone cases), trauma-related arthritis (6 cases) and neoplasia lysis [12, 13]. A high RANKL/OPG ratio has also been (1 case). Thus, 83 patients were analyzed: 33 with RA, 32 observed in the synovial fluid (SF) and serum of patients with SpA and 18 with OA (Fig. 1). The SpA group con - with RA and SpA, but the clinical relevance of this obser- sisted of patients with psoriatic arthritis (PsA, n = 13), vation is still unclear [14–16]. It is also known that the ankylosing spondylitis (AS, n = 7), enteropathic arthri- expression of RANKL in the synovial tissue of patients tis (EpA, n = 7) and reactive arthritis (RA, n = 5). All with RA is higher in active disease than in less-active dis- patients signed informed consent forms, and the study ease and in SpA and OA [17, 18]. In patients with OA, was approved by the Research Ethics Committee of the the serum RANKL/OPG ratio may be related to more HCRP-USP (opinion number: 59784122.8.0000.5440). severe forms of the disease [19]. There are few comparative data regarding the levels Clinical and laboratory evaluations of these proteins in the SF of individuals with chronic Patient information including sex, age, time since diagno- arthropathies. We compared the synovial concentrations sis, associated diseases and medication use was collected. of RANKL and OPG, in addition to the RANKL/OPG For patients with RA, disease activity was evaluated as ratio, in patients with RA, SpA and OA. In addition, we the Disease Activity Score 28 (DAS28) [23]. All patients evaluated whether the synovial levels of these proteins had their levels of rheumatoid factor (RF) and anti-cyclic are correlated with markers of inflammatory activity, Q uaresma et al. Advances in Rheumatology (2023) 63:13 Page 3 of 8 Osteoprotegerin, Duo Set Human TRANCE/RANKL, R&D Systems, Minnesota, USA). Statistical analysis Absolute numbers and percentages were compared with Fisher’s exact test. Continuous variables are presented as the mean (or median) and standard deviation (or inter- quartile range). ANOVA (or the Kruskal‒Wallis test) was used to compare the serum levels of RANKL and OPG and the RANKL/OPG ratio. The Pearson or Spearman correlation coefficients (if the sample distribution was different from a normal distribution) were used to evalu - ate the degree of correlation between RANKL and OPG values and clinical and laboratory parameters. For all tests, p < 0.05 was considered statistically significant. Results Of the 83 patients recruited, 54 (65%) were women, and the median age was 56 (18–82) years. The clinical and Fig. 1 Study flowchart laboratory characteristics of the patients are shown in Table 1. Of the 65 patients with immune-mediated arthropa- citrullinated peptide (anti-CCP) antibody previously thy, 20 (31%) had been diagnosed less than 2 years prior, measured. For the SpA group, DAS28 was used to evalu- 6 were treatment-naive, 16 were on monotherapy with ate disease activity whether the disease was restricted to disease-modifying antirheumatic drugs (DMARDs) peripheral joints. If the patients had axial involvement, and 33 (51%) were treated with biological DMARDs ASDAS-CRP was used to assess disease activity [24]. (bDMARDs), both with and without concomitant syn- In order to evaluate if SF levels OPG and RANKL were thetic DMARD use. Among the DMARDs, methotrexate influenced by disease activity, RA and SpA groups were was the most used, followed by leflunomide and sul - further divided taking into account values of DAS28 ≥ 3.2 fasalazine. Among the bDMARDs, anti-tumor necrosis or ASDAS-CRP ≥ 2.1 (for axial SpA only). Regarding the factor (TNF) drugs were the most frequent. No patient OA group, activity evaluation was not performed because was using prednisone at a dosage greater than 5 mg/day. there is no specific score. Each patient was classified The RA group had a median disease duration of 4 according to the Kellgren-Lawrence system to assess the (2–11) years. Active smoking, positive RF, positive stage of OA at the punctured knee [25]. anti-CCP antibody and erosion on hand or knee radi- The erythrocyte sedimentation rate (ESR) and C-reac - ography were observed in 40%, 70%, 78% and 61% of tive protein (CRP) level were determined for all patients patients, respectively. For 73% of the patients, we found on the day of arthrocentesis. Radiographs of the hands an increase in the ESR and/or CRP level. The median and/or knees were analyzed by a single physician mem- ESR was 23 (7–37) mm/h, and the median CRP level was ber of the team (SCLA) to establish the presence of ero- 0.95 (0.4–3.1) mg/dL. Fifteen (45%) of RA patients had a sion or subchondral cysts. The physician was blinded to DAS28 ≥ 3.2. the information of the recruited patients. In the SpA group, the mean disease duration was 4 (0.87–7.7) years. The ESR and/or CRP level were increased in 75% of these patients, and 44% had bone Experimental procedures erosions on hand or knee radiography. DAS ≥ 3.2 or The SF was collected in an EDTA tube and analyzed ASDAS-CRP ≥ 2.1 was found in 14 (44%) of the SpA within two hours after collection to determine the total patients. In the OA group, the mean disease duration was and differential leukocyte counts. A 1 mL aliquot of 5.6 (0.5–16) years, and 78% had been diagnosed more SF was stored at − 80 °C until the day of the RANKL than two years prior and were in an advanced stage of and OPG measurements. Levels of RANKL and OPG joint involvement (Kellgren-Lawrence classification III or in the samples were determined by ELISA accord- IV). Subchondral cysts or bone erosions in hand or knee ing to the manufacturer’s protocols (Duo Set Human x-rays were observed in 8 (44%) patients. Quaresma et al. Advances in Rheumatology (2023) 63:13 Page 4 of 8 Table 1 Clinical, laboratory and radiographic characteristics Rheumatoid arthritis Spondyloarthritis (n = 32) Osteoarthritis (n = 18) p-value (n = 33) Demographics Female [n (%)] 28 (85) 8 (25) 18 (100) N/A Age [years; median (IQR)] 57.0 (20–82) 46.5 (18–74) 68.0 (49–82) N/A Time of disease < 2 years [n (%)] 8 (24) 12 (37) 4 (22) N/A Comorbidities Smoking [n (%)] 13 (40) 5 (15) 5 (28) N/A Cardiovascular diseases [n (%)] 21 (64) 13 (40) 12 (66) N/A Diabetes mellitus [n (%)] 2 (6) 3 (9) 3 (16) N/A Dyslipidemia [n (%)] 4 (12) 3 (9) 2 (11) N/A Obesity [n (%)] 4 (12) 2 (6) 5 (27) N/A Fibromyalgia [n (%)] 5 (15) 1 (3) 2 (11) N/A Laboratory findings CRP [mg/dL; median (IQR)] 0.95 (0.4–3.1) 1.2 (0.6–6.3) 1.9 (0.5–3.4) ns CRP > 1.0 [mg/dL; n (%)] 16 (48) 17 (53) 10 (55) ns ESR [mm/h; median (IQR)] 23 (7–37) 19 (8–40.7) 20 (6–26) ns ESR > 20 [mm/h; n (%)] 18 (54.5) 15 (46.8) 7 (38.8) ns Cell count [/mm ; median (IQR)] 7675 (862–16950) 8400 (2475–16,825) 800 (250–1225) < 0.01 Neutrophils [/mm ; median (IQR)] 77 (62–85) 72 (52–88) 70 (43–76) ns Medications Methotrexate [n (%)] 8 (25) 2 (6) – ns Leflunomide [n (%)] 8 (25) 1 (3) – ns Sulfasalazine [n (%)] 1 (3) 5 (28) – ns TNF‑blocker [n (%)] 10 (30) 16 (50) – ns Non TNF‑blocker [n (%)] 6 (18) 1 (3) – ns IQR interquartile range, CRP C-reactive protein, ESR Erythrocyte sedimentation rate The SF leukocyte count was higher in patients with parameters are shown in Table 3. In patients with RA, immune-mediated chronic arthropathy than in OA there was a positive correlation between the SF cell count patients. There was no difference between the RA and and RANKL level (r = 0.59, p < 0.05) and the RANKL/ SpA groups (Table 1). OPG ratio (r = 0.55, p < 0.05). There was no correlation The levels of RANKL and OPG and the RANKL/OPG between RANKL and OPG levels and CRP, erosion or ratio in the SF of the 3 groups are shown in Table 2. DAS28. In patients with OA, there was a strong positive There was no significant difference between the groups. correlation between CRP level and the RANKL/OPG The correlations with the laboratory and radiographic ratio (r = 0.82, p < 0.05), but there was no correlation with Table 2 Comparisons of RANKL, OPG and RANKL/OPG according to disease activity RA (n = 33) SpA (n = 32) OA (n = 18) p-value* DAS28 ≥ 3.2 (n = 15) DAS28 < 3.2 (n = 18) DAS28 ≥ 3.2 or DAS28 < 3.2 or All patients (n = 18) ASDAS-CRP ≥ 2.1 ASDAS-CRP < 2.1 (n = 14) (n = 18) RANKL (pg/mL; 85 ± 61 54 ± 31 66 ± 43 53 ± 24 65 ± 36 0.45 mean ± SD) OPG (pg/mL; 18,840 ± 11,460 14,800 ± 10,960 11,310 ± 12,160 21,250 ± 14,270 18,160 ± 11,040 0.16 mean ± SD) RANKL/OPG (x10 ) 38.6 ± 11.1 11.6 ± 10.4 16.7 ± 20.8 4.7 ± 5.3 5.6 ± 5.5 0.62 *ANOVA; SD Standard deviation Q uaresma et al. Advances in Rheumatology (2023) 63:13 Page 5 of 8 Table 3 Correlations of RANKL, OPG and RANKL/OPG with synovial levels of RANKL or OPG or the RANKL/OPG laboratory and radiographic parameters ratio between the groups. In patients with RA, the synovial RANKL level and the RANKL OPG RANKL/ OPG RANKL/OPG ratio were significantly correlated with the Rheumatoid arthritis cell count in the SF. There was no statistical significance CRP r* 0.15 − 0.20 0.13 with other parameters of disease activity or severity, such p 0.51 0.26 0.54 as markers of inflammatory activity, DAS28 and erosions Cell count r 0.59 − 0.08 0.55 on hand radiography. Unlike what was observed in our p 0.004 0.68 0.008 study, Ellabban et al. detected higher serum and synovial Bone erosions r − 0.22 0.12 − 0.40 RANKL levels in patients with RA than in patients with p 0.37 0.52 0.09 OA and a significant correlation between synovial lev - DAS28 r 0.30 0.28 0.21 els and parameters of disease severity and activity [26]. p 0.12 0.14 0.28 Skoumal et al. found that the OPG and RANKL levels in Spondyloarthritis the SF were negatively correlated in RA, showing signifi - CRP r 0.01 − 0.13 0.18 cantly low OPG and high RANKL levels [16]. In addition, p 0.98 0.52 0.58 they observed that the OPG/RANKL ratio was signifi - Cell count r − 0.11 0.22 − 0.09 cantly related to radiographic changes. Haynes et al., in p 0.72 0.28 0.77 a semiquantitative and quantitative analysis via immu- Bone erosions r 0.30 − 0.19 0.20 nostaining, showed that the expression level of OPG in p 0.7 0.38 0.56 synovial tissue was markedly decreased in patients with DAS28 or ASDAS‑ CRP r − 0.35 0.08 0.02 active RA compared with patients with inactive RA or p 0.054 0.79 0.89 OA or with healthy individuals [18]. Similarly, Kong et al. Osteoarthritis demonstrated that the SF OPG levels were lower in RA CRP r 0.41 − 0.41 0.82 than in OA [27]. The lower synovial OPG may reflect a p 0.28 0.17 0.006 less protective effect on the bone, leading to earlier and Cell count r − 0.29 − 0.12 − 0.09 more pronounced bone destruction, as occurs in RA. The p 0.48 0.71 0.83 amount of RANKL in synovial tissue is higher in indi- Subchondral cysts or bone r 0.36 − 0.33 0.51 viduals with active RA than in individuals with controlled erosions p 0.25 0.20 0.09 RA and individuals with SpA and OA [18]. The RANKL/ Total OPG ratio is significantly higher in rheumatoid synovial CRP r 0.40 − 0.26 0.27 tissue than in the synovial tissues of other chronic inflam - p 0.008 0.025 0.08 matory arthropathies, especially reactive arthritis [28]. Subchondral cysts or bone r 0.05 − 0.09 0.04 We found a positive correlation between the SF cell erosions p 0.74 0.74 0.78 count and the RANKL level and RANKL/OPG ratio in RA. In fact, the joint infiltrate of inflammatory cells is * Spearman’s correlation; CRP C-reactive protein; For statistical significance [bold], p < 0.05 greater in active RA than in less active disease or other inflammatory arthropathies [10]. The presence of cells in the SF, such as neutrophils and B and T cells, induces increased RANKL expression, which stimulates activa- the other parameters evaluated. In the SpA group, no sta- tion, proliferation and interaction with dendritic cells, tistically significant correlations were observed. contributing to bone remodeling [29, 30]. When analyzing the samples together, considering all In the joint analysis of the 3 groups, we found that patients in the study, we observed that the CRP level was the CRP level was negatively correlated with OPG weakly and negatively correlated with the OPG level (r and positively correlated with RANKL, suggesting the = − 0.26, p = 0.02) and moderately positively correlated important role of this marker in the pathophysiology with the RANKL level (r = 0.40, p = 0.008) (Fig. 2). of synovial inflammation. Denosumab, a monoclonal antibody that specifically binds to and subsequently Discussion inactivates RANKL, was evaluated in patients with RA This study aimed to quantify the RANKL and OPG levels [31–33]. Hu et al., in a meta-analysis with a total of 1758 in the SF of patients with RA, SpA and OA and evaluate patients evaluating the presence of bone erosion and their correlations with clinical and laboratory parameters joint space reduction, showed that denosumab signifi - of each disease. There was no statistical difference in the cantly increased the percentage of bone mineral density (BMD) and reduced the radiographic damage score [34]. Quaresma et al. Advances in Rheumatology (2023) 63:13 Page 6 of 8 Fig. 2 Correlation between CRP and the levels of OPG and RANKL for the 83 patients Our results showed a strong positive correlation of bone involvement, with extensive new bone formation between the RANKL/OPG ratio and the CRP level in the former and marked focal bone erosions in the lat- in patients with osteoarthritis. High levels of syno- ter [38]. This similarity was also observed by Vandooren vial RANKL were found in individuals with OA; within et al. when analyzing the synovial tissue of patients with this group, the levels were higher in patients with ero- PsA, other SpAs and RA [14]. Our data are in agreement sive nodal OA than in patients with nonerosive OA and with this study and may suggest that the differences in the were correlated with the presence of Heberden’s and pattern and extent of bone erosions between these dis- Bouchard’s nodes, the Kellgren-Lawrence score and ero- eases are not related to the synovial expression of these sive changes found in both hands [26]. Pilichou et al. also proteins. These results should be analyzed with caution demonstrated a correlation between the RANKL/OPG due to the heterogeneity of the samples in both studies. ratio and disease severity in primary OA, but only in Data on AS are conflicting. In 2019, Chen et al., in a serum, not in the SF [19]. meta-analysis with 1592 patients and 1064 healthy con- Regarding systemic inflammation, we found elevated trols, concluded that the serum levels of OPG and and similar values of serum CRP and ESR among the RANKL and the RANKL/OPG ratio were significantly groups. OA group had higher frequencies of obesity and higher in AS patients than in healthy controls [39]. A diabetes mellitus. Obesity in women is a well-known subgroup of patients with high inflammatory activity condition related to elevation of serum CRP due to a marker levels, ESR and CRP levels, shorter disease dura- low-grade systemic inflammation [35], resulting in val - tion and high disease activity indexes had higher serum ues above 1.0 mg/dL. The low-grade inflammation due to levels of OPG and RANKL. The authors concluded that diabetes mellitus is associated with serum CRP elevations OPG, RANKL and the RANKL/OPG ratio can be used as [36] and may have contributed to our results. Regarding potential biomarkers for AS [40]. ESR, values of OA group similar to those of RA and SpA In our sample, 59 of the 65 patients with immune- can be associated to the totality of women in this group mediated rheumatic disease were regularly using and the mean age considerably higher. Female gender DMARDs, which may have interfered with our results. and age are two conditions known to elevate ESR [37]. In a study with 50 patients with RA, Vassev et al. evalu- Besides, we should mention that we enrolled patients ated the effect of anti-TNF therapy in combination with with Kellgren-Lawrence score III or IV and this long- methotrexate on bone remodeling and osteoclastogene- term augments the chance of relevant synovial inflamma - sis. After 15 months of treatment, they observed a reduc- tion [8]. tion in resorption markers and RANKL/OPG ratio and In patients with SpA, we did not find correlations an increase in bone formation markers, regardless of the between the RANKL and OPG levels and the clinical type of anti-TNF drug used [40]. The high frequency of and radiological parameters evaluated. The expression treatments with bDMARDs (51%) in our cohort may of OPG and RANKL was similar to that of patients with explain the similarity on SF levels of OPG and RANKL RA, despite the marked differences between the pattern we found. Q uaresma et al. Advances in Rheumatology (2023) 63:13 Page 7 of 8 References Our study has some limitations, such as the nonconcom- 1. Tateiwa D, Yoshikawa H, Kaito T. Cartilage and bone destruction in itant evaluation of serum RANKL and OPG levels. The het - arthritis: pathogenesis and treatment strategy: a literature review. 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This study was supported by Fundação de Amparo à Pesquisa do Estado de The ratio of circulating osteoprotegerin to RANKL in early rheumatoid São Paulo (FAPESP) (Grant: FAPESP‑ CRID 2013/08216‑2) (São Paulo, SP, Brazil); arthritis predicts later joint destruction. Arthritis Rheum. 2006;54:1772–7. Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 16. Skoumal M, Kolarz G, Haberhauer G, Woloszczuk W, Hawa G, Klingler A. (Grant: 425075/2016‑8) (Brasilia, DF, Brazil). Osteoprotegerin and the receptor activator of NF‑kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding Availability of data and materials rheumatoid arthritis and osteoarthritis. Rheumatol Int. 2005;26:63–9. All data generated or analysed during this study are included in this published 17. Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM. Osteopro‑ article. tegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology. 2001;40:623–30. Declarations 18. Haynes DR, Barg E, Crotti TN, Holding C, Weedon H, Atkins GJ, et al. Osteo‑ protegerin expression in synovial tissue from patients with rheumatoid Ethics approval and consent to participate arthritis, spondyloarthropathies and osteoarthritis and normal controls. The local ethics committee approved the study (CAAE: 59784122.8.0000.5440). Rheumatology. 2003;42:123–34. All patients provided written informed consent. 19. Pilichou A, Papassotiriou I, Michalakakou K, Fessatou S, Fandridis E, Papachristou G, et al. High levels of synovial fluid osteoprotegerin (OPG) Consent for publication and increased serum ratio of receptor activator of nuclear factor‑kappa Not applicable. B ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis. 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Rheumatology. 2016;55(Suppl 2):ii56–ii60. 39. Chen M, Hu X, Wu M, Yang J, Han R, Ma Y, et al. Serum levels of OPG, RANKL, and RANKL/OPG ratio in patients with Ankylosing Spondylitis: a systematic review and Meta‑analysis. Immunol Invest. 2019;48:490–504. 40. Jura‑Półtorak A, Szeremeta A, Olczyk K, Zoń‑ Giebel A, Komosińska‑ Vassev Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : K. Bone metabolism and RANKL/OPG ratio in rheumatoid arthritis women treated with TNF‑α inhibitors. 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Journal
Advances in Rheumatology – Springer Journals
Published: Mar 15, 2023
Keywords: Arthritides; Rheumatoid arthritis; Spondyloarthropathy; Osteoarthrosis; OPGL protein; RANKL protein