. 2022 May 21;18(9):3731–3746. doi: 10.7150/ijbs.67587

Table 1.

List of studies on the relationship between RA and YKL-40 (chitinase-3-like protein-1, human cartilage glycoprotein-39).

Authors, year	Study design	Main study findings
van Bilsen JH et al, 2004 ²⁰	-PBMCs obtained from RA patients were stimulated in vitro with HC gp-39. -Elispot analyses were used to analyze the production of cytokines.	• HC gp-39 may have anti-inflammatory phenotype in healthy individuals. • gp-39 immune response in RA patients has pro-inflammatory phenotype.
Hakala BE et al, 1993. ²¹	-HC gp-39 was isolated using PCR and western blotting. -Northern blotting and RT-PCR was used to detect HC gp-39 mRNA both in synovial membranes and in cartilage acquired from patients with RA.	• Purified and sequenced HC gp-39 has regions similar to three other mammalian secretory proteins. • HC gp-39 mRNA was present in articular chondrocytes.
Baeten D et al, 2000 ¹⁴	-Immunohistochemistry and flow cytometry were used to study expression of HC gp-39 in synovium and PBMCs. -Synthesis and secretion of HC gp-39 were evaluated by RT-PCR and ELISA.	• HC gp-39 expression was more significant in RA patients compared to spondyloarthropathy patients and healthy controls. • gp-39 level is correlated with the degree of joint destruction in RA.
Kirkpatrick RB et al, 1997 ¹⁵	-In situ hybridization was used to detect HC gp-39 mRNA in macrophages obtained from ST of 5 RA patients.	• HC gp-39 is expressed in primary human macrophages. • Its expression is closely related to differentiation of monocytes into macrophages in RA patients.
Harvey S et al, 1998 ¹⁶	-Sandwich-type ELISA was used to compare serum Chondrex (HC gp-39) in healthy controls and in arthritis groups.	• Chondrex (HC gp-39) values are highly increased in active RA patients compared to healthy controls and inactive RA groups. • Chondrex levels may be an effective marker in estimating RA disease activities. • By assessing Chondrex values of RA patients, the effectiveness of the DMARD therapy can be identified.
Verheijden GF et al, 1997 ²²	-Self-reactive peptides within HC gp-39 were tested for their ability to induce mononuclear cell responses in RA patients or healthy donors' peripheral blood. -Native HC gp-39 was injected into mouse model to study its ability to develop arthritis.	• HC gp-39-derived motif-based peptides were selectively recognized by peripheral blood T cells from RA patients. • HC gp-39-derived motif-based peptides are associated with the development of a chronic, relapsing arthritis.
Patil NS et al, 2001 ²³	-Antigen presentation assays using DR*0401-restricted T cell hybridomas made by transgenic mice with HC gp-39.	• HLA-DM has a crucial role in presenting HC gp-39 to CD4+ T cell hybridomas. • HLA-DM dependent pathway has inference for HC gp-39 presentation in RA.
Baeten D et al, 2004 ²⁴	-Immunostaining with monoclonal antibody 12A on synovial joints captured from RA patients and healthy controls.	• HC gp-39 is correlated with histologic characteristics of inflammation in RA joints. • Monoclonal antibody 12A staining can be a novel immune-pathologic diagnostic tool for RA.
Kavanaugh, A et al, 2003 ²⁵	-31 persistent RA patients with positive HLA-DRB1*0401 were randomized to 7 infusions of AG4263 for 6 weeks.	• AG4263 is a soluble complex of Org36601 which is derived from HC gp-39. • Infusion of AG4263 with methotrexate was safe and well tolerated for persistent RA disease activity without generalized immunosuppression.
Petersson et al., 2006 ²⁶	-Analysis of cultured chondrocyte samples from RA patients, OA patients, and healthy subjects.	• Both AVP and PTHrP increase YKL-40 secretion in RA chondrocytes. • AVP decreases YKL-40 secretion in healthy and OA chondrocytes. • AVP and PTHrP influence RA pathogenesis as proinflammatory hormones.
Volck et al., 1998 ²⁷	-Immunoelectron microscopy and immunohistochemistry studies on neutrophils and bone marrow cells.	• Synovial fluid of active RA patients contains high levels of YKL-40 as well as abundant neutrophils, which are thought to be important in joint destruction. • YKL-40 released from neutrophils may play a role in tissue remodeling or degradation in various inflammatory diseases including RA.
Vos et al., 2000 ²⁸	-Comparison of plasma HC gp-39 levels in 50 RA, 51 OA, 24 SLE, 26 IBD patients and 49 healthy controls by one-way ANOVA.	• RA, OA, SLE, and IBD patients have significantly higher serum levels of HC gp-39 than healthy controls.
Harvey et al., 2000 ²⁹	-Analysis of sYKL-40 by ELISA in 57 ERA patients over 19 months	• sYKL-40 does not provide any additional information that would not be attainable by means of conventional biochemical measurements of disease activity.
Sekine et al., 2001 ³⁰	-ELISA assay and western blotting of serum samples YKL-39 and YKL-40 from 87 RA and 47 SLE patients.	• YKL-39 and YKL-40 share more than 50% amino acid and nucleotide sequence homology. • YKL-39, unlike YKL-40, which is speculated to be an autoantigen in RA, does not seem to be a sensitive marker for RA diagnosis. • The immune response to YKL-39 was shown to be independent of that to YKL-40.
Steenbakkers PG et al, 2003 ³¹	-Monoclonal antibodies that bind DRαβ10401/HC gp-39(263-275) complexes were used to investigate the MHC-Ag complexes, and expression of HC gp-39 was studied in ST of DRαβ10401-positive RA patients by immunohistochemistry.	• The HC gp-39(263-273) epitope is specifically essential for binding of MHC protein. • Among 5 mAb studied, mAb 12A has the most specificity for DRαβ1*0401/HC gp-39(263-275) complexes, and therefore mAb 12A was used to detect MHC/peptide/TCR complexes in the synovium of RA patients.
Matsumoto et al., 2001 ³²	-Assessment of sYKL-40, sIGF-I, and sIL-6 levels in 72 RA patients and 40 healthy subjects measured by ELISA.	• RA patients had significantly higher sYKL-40 levels than the healthy controls. • sYKL-40 levels were positively correlated with sIL-6 and CRP levels but negatively correlated with sIGF-I. • sYKL-40 levels correlated with radiological score and severity of functional disability but not with joint pain.
Johansen et al, 2001 ³³	-Analysis of sYKL-40 samples from RA patients treated with DMARDs for 36 months measured by ELISA.	• sYKL-40 levels in ERA patients were significantly correlated with radiological progression determined by the Larsen score • sYKL-40 may provide information independent of CRP on disease activity.
Johansen et al., 1999 ³⁴	-1-year longitudinal study of sYKL-40 obtained from 156 RA patients by RIA.	• In RA, sYKL-40 levels correspond to disease activity: levels decreased significantly in active patients who became clinically inactive, while levels increased in inactive patients who developed active RA.
Volck et al., 2001 ³⁵	-Analysis of serum and synovial fluid YKL-40and other biochemical markers determined by RIA and ELISA.	• YKL-40 was detected in the synovial membrane of RA and OA patients. • The number of YKL-40 positive cells in the inflamed synovial membrane is positively correlated with the severity of inflammation. • Intra-articular glucocorticoid injection was followed by a decline in sYKL-40 levels.
Vos K et al, 2000 ³⁶	-Growth with 5 different HC gp-39 derived peptides followed by measuring multiplication of PBMC as well as recording disease activity score in RA, SLE, IBD, OA and healthy controls.	• In autoimmune diseases including RA, HC gp-39 derived peptides are the objects of T cell immunity. • Especially HC gp‐39 derived peptide 259-271 are known to be correlated with disease severity in RA.
den Broeder A et al, 2002 ³⁷	-Univariate and multivariate analyzes were used to assess the association between serum markers of radiological progression and cartilage and synovial membrane turnover (HC gp-39). -Integrated measures of disease activity.	• Long term TNF-alpha neutralization decreased the levels of HC gp-39, in RA patients.
Peltomaa et al., 2001 ³⁸	-Analysis of sYKL-40 in 52 early onset RA patients by ELISA during a 2-year prospective follow-up	• Baseline sYKL-40 levels prior to anti-rheumatic therapy were significantly higher in ERA patients compared to healthy controls. • sYKL-40 is an inflammatory marker that correlates with disease activity, but does not have predictive value concerning radiographic progression or clinical course.
Combe B et al, 2001 ³⁹	-A cohort study of 191 RA patients conducted for three years.	• The average odds ratio of YKL-40was 1.3(p=0.5) in predicting radiographic progression.
Fusetti F et al, 2003 ⁴⁰	-Analysis of crystallized structures of HC gp-39 by using the hanging drop vapor-diffusion method with recombinant HC gp-39.	• HC gp-39 is apparently eligible autoantigen of RA and though its exact physiological function is unexplained. • HC gp-39, epitopes 259-271 and 263-275 are associated with disease activity. • Even if region 266-275 leads to the protein surface, residues 259-265 placed in the near-by of the chitin-binding groove.
Knudsen et al., 2009 ⁴³	-Repeated measurements of pIL-6, pVEGF, and sYKL-40 for 25 Danish RA patients during treatment.	• In treatment of RA, 18 of 25 patients had significantly decreased pIL-6, pVEGF, and sYKL-40 which were significantly elevated before treatment.
Tsark EC etval., 2002 ⁴⁴	-Blood monocyte-derived dendritic cell and macrophage were incubated with native human CII, HC gp39, and synovial fluid from RA patients. and the comparison with T cell hybrids produced by immunizing DR4-transgenic mice with CII 259-263 and HC gp39^263-275 peptides.	• Human ex vivo differentiated dendritic cell and macrophage that were incubated with synovial fluid from RA patients differentially presented CII and HC gp39 MHC II epitopes. • CII and HC gp39 might be important autoantigens in RA immunopathology and show different mechanisms of their presentation by dendritic cell and macrophage.
Boots AM et al., 2007 ⁴⁵	-Competition binding assay was used to map epitopes that strongly bind to T cell hybridomas obtained from HC gp-39-immunized HLA-DR4 transgenic mice.	• Anchor variant peptide can modify antigen-specific, pro-inflammatory response in HLA-DR4 transgenic mice in a dampening fashion.
van Lierop Mj et al., 2007 ⁴⁶	-MIA and HC gp-39 levels in SF and ST were determined by enzyme-linked immunosorbent assay and immunohistochemistry. -IL-2 production of T cell hybridomas generated by immunizing DR4-transgenic mice with HC gp-39 or MIA were used to study presentation of MIA and HC gp-39 by SF cells.	• HC gp-39 and MIA were found in the SF and ST of patients with arthritis, and they were mainly presented by HLA-DR myeloid dendritic cells and B cells.
Li et al., 2017 ⁴⁷	-In vivo study using recombinant human YKL-40.	• YKL-40 activates the FAK/PI3K/Akt pathway, thereby inducing the production of IL-18 in osteoblasts and the inhibition of miR-590-3p. • Stimulation of EPC angiogenesis, subsequently promoting inflammation, a process critical to the pathogenesis of RA.
Kazakova et al., 2017 ⁴⁸	-Analysis of serum and synovial YKL-40, TNF-α, IL-6, and IL-1β samples obtained from 39 RA patients using ELISA assay.	• IL-1β is the most important factor involved in the inflammatory process in RA • TNF-α might induce secretion of YKL-40 from chondrocytes. • Serum and synovial YKL-40, IL-1β, and TNF-α levels are strongly correlated, suggesting that these molecules together play an important role in RA pathogenesis and disease activity. • No correlation exists between YKL-40 and IL-6 levels.
Nielsen et al., 2011 ⁴⁹	-Analysis of serum and whole blood samples from 308 RA patients and 605 healthy blood donors.	• The g.-131 (C > G) promoter SNP in the CHI3L1 gene is strongly associated with the serum concentration of YKL-40 in both RA patients and in healthy controls. • The g.-131 (C > G) promoter SNP does not appear to be a direct risk factor of RA itself.
Baeten D et al., 2004 ⁵⁰	-Synovial biopsy samples were gathered for diagnostic evaluation from 154 patients.	• HLA-DR shared epitope (HC gp-39(263-275) complexes) and crystal deposition had positive predictive values for diagnosis of >90% in patients for atypical RA patients.
Brahe et al., 2018 ⁵³	-Two investigator-initiated RCTs performed on treatment-naïve ERA patients.	• sIL-6, sYKL-40, and pVEGF levels were significantly correlated with DAS28 at baseline. • They did not appear to be predictive of either clinical remission or radiographic progression.
Väänänen et al., 2017 ⁵⁴	-RCT (NEO-RACo study) on 99 ERA patients undergoing DMARD therapy for 26 weeks.	• Baseline pYKL-40 levels in ERA patients showed a positive correlation with disease activity as well as with IL-6 and MMP-3 levels. • During DMARD treatment, YKL-40 levels decreased significantly, which appears to be directly related to the anti-rheumatic effect of DMARDs. • YKL-40 could potentially be used as a biomarker of disease activity in both ERA and RA patients undergoing active DMARD treatment.
Turkyilmaz et al., 2013 ⁵⁵	-Cross-sectional study of 42 ERA patients and 35 healthy subjects. -Evaluation of arterial stiffness by cf-PWV and IMT-C by carotid ultrasonography.	• The patients' sYKL-40 levels were strongly correlated with both cf-PWV and DAS28. • sYKL-40 levels could reflect early atherosclerosis, a major factor that contributes to mortality, as well as disease activity in ERA patients.
Kazakova et al., 2012 ⁵⁶	-Comparison of YKL-40 levels in serum and synovial fluid and ultrasonographic findings obtained from 25 RA patients and 40 healthy subjects.	• The Bulgarian RA patients were found to have significantly higher sYKL-40 levels than the healthy subjects. • There is a positive correlation between YKL-40 in serum and synovial fluid and sonographic parameters.
Knudsen et al., 2008 ⁵⁶	-Analysis of biochemical measurements, radiographs, and MRI images obtained from 51 ERA patients and 21 PA patients.	• pIL-6, sYKL-40, pVEGF, CRP, and ESR were elevated in RA patients but not in PA patients. • Only pIL-6 was related to treatment response and progressive erosive disease in ERA; sYKL-40 showed no association.
Bakker M et al., 2012 ⁵⁷	-Twelve biomarkers, including YKL-40, were used to calculate the MBDA score of RA patients.	• YKL-40 was one of the markers of the MBDA score designed to measure RA disease activity. • The MBDA score showed a significant correlation in measuring disease activity of RA.
Tanaka Y et al., 2014 ⁵¹	-Analysis of HC gp-39 serum levels and mRNA expressions using ELISA and RT-PCR in GPI-induced arthritis.	• On the early phase of GPI-induced arthritis, HC gp-39 mainly showed in CD4+CD25+FoxP3+ Treg cells. • Addition of recombinant HC gp-39 blocked GPI-specific T cell proliferation and cytokine production, which means HC gp-39 in CD4+ T cells might play a regulatory role in early RA.
Knudsen et al., 2006 ⁵⁸	-1-year pilot study of sYKL-40 in 20 RA patients undergoing 52 weeks of infliximab and concomitant methotrexate therapy	• High baseline pIL-6 is significantly related to radiographic joint destruction progression. • It is unknown whether sYKL-40, independent of ESR, can provide information on joint destruction and disease activity in RA patients being treated with infliximab.
Syversen et al., 2009 ⁵⁹	-Cohort study of 238 RA patients followed for 10 years. -Analysis of serum samples and radiograph data.	• In contrast to sCTX-1 levels, sYKL-40 levels are weakly associated with radiographic progression and inflammation in RA. • sYKL-40 will likely be much less useful as a prognostic marker of RA.
Landewé RB et al., 2010 ⁶⁰	-A phase II, 13-week multicenter, double-blinded RCT on patients with RA to receive either intranasal applications of placebo. or fully human, recombinant HC gp-39 (Org39141) in differential doses once a week.	• Intranasal administration of Org39141 was proven to be safe but showed no efficacy over placebo.
Wolvers DA et al., 1999 ⁶¹	-Mouse model was intra-nasally administered with OVA and HC gp-39 for tolerance induction. -Lymph nodes were surgically removed and re-transplanted to see importance of lymph nodes in tolerance induction.	• Certain lymph nodes that drain the nasal mucosa are essential in intranasal tolerance induction of model Ag (OVA) and HC gp-39. • Therapeutic potential of intranasal administration of HC gp-39 in RA.

Abbreviations: RA: rheumatoid arthritis; PBMC: peripheral blood mononuclear cell; HC gp-39: human cartilage glycoprotein-39; PCR: polymerase chain reaction; RT-PCR: reverse transcription polymerase chain reaction; ELISA: enzyme-linked immunosorbent assay; ST: synovial tissue; DMARD: disease-modifying anti-rheumatic drugs; HLA: human leukocyte antigen; OA: osteoarthritis; AVP: arginine vasopressin; PTHrP: parathyroid hormone-related peptide; SLE: systemic lupus erythematosus; IBD: inflammatory bowel disease; ANOVA: analysis of variance; sYKL-40: serum YKL-40; ERA: early rheumatoid arthritis; MHC: major histocompatibility complex; Ag: antigen; mAb: monoclonal antibody; TCR: T-cell receptor; sIGF-I: serum insulin-like growth factor I; sIL-: serum interleukin; CRP: C-reactive protein; RIA: radioimmunoassay; TNF: tumor necrosis factor; pIL-: plasma interleukin; pVEGF: plasma vascular endothelial growth factor; CII: type II collagen; MIA: melanoma inhibitory activity; SF: synovial fluid; IL-: interleukin; FAK: focal adhesion kinase; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; miR: microRNA; EPC: endothelial progenitor cell; SNP: single nucleotide polymorphism; RCT: randomized controlled trial; DAS28: disease activity score (28 joints); pYKL-40: plasma YKL-40; MMP-3: matrix metalloproteinase-3; cf-PWV: carotid to femoral pulse wave velocity; IMT-C: carotid intima media thickness; MRI: magnetic resonance imaging; PA: polyarthritis; ESR: erythrocyte sedimentation rate; MBDA: multi-biomarker disease activity; GPI: glucose-6-phosphate isomerase; FoxP3: forkhead box protein 3; Treg cell: regulatory T cell; sCTX-1: serum collagen cross-linked C-telopeptide; OVA: ovalbumin.