Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglycan and decorin in patients with rheumatoid arthritis or other joint diseases

Polgar, A. A.; Falus, András; Koo, Eunhee; Újfalussy, Ilona; Seszták, Magdolna; Szüts, I Ldikó; Konrad, K.; Hodinka, László; Bene, Eszter; Mészáros, György; Ortutay, Zs.; Farkas, É.; Paksy, András; Buzás, Edit I.

doi:10.1093/rheumatology/keg168

Cited by 49 publications

(39 citation statements)

References 25 publications

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“…Depleted PG content is observed in the articular cartilage of RA patients accompanied with fibrillar fragmentation [19]. Whilst elevated levels of biglycan antibodies have been detected in serum and synovial fluid of RA patients [20] and they are considered to be early markers of this disease. However the exact role of these antibodies in initiation and development of the drastic changes RA causes to cartilage has remained unclear as does the specific mechanism of tissue destruction.…”

Section: Resultsmentioning

confidence: 99%

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

Antipova

Orgel

2012

PLoS ONE

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Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. In RA cases, the immune response to inflammation causes synovial fibroblasts, monocytes and macrophages to produce cytokines and secrete matrix remodeling enzymes, whereas B cells are stimulated to produce immunoglobulins. The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo.

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Section: Resultsmentioning

confidence: 99%

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

Antipova

Orgel

2012

PLoS ONE

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“…Figure 6, A and B, shows that 1,25(OH) 2 D3 reduced mRNA and protein levels of fibromodulin in HuLM cells, which suggests the potential role of 1,25(OH) 2 D3 in regulating the ECM. Furthermore, biglycan is a small, leucine-rich proteoglycan in ECM that influences differentiation and proliferation processes [68], and we tested whether 1,25(OH) 2 D3 can regulate biglycan expression in HuLM cells. Our results (Fig.…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Reduces Extracellular Matrix-Associated Protein Expression in Human Uterine Fibroid Cells1

Halder

Osteen

Al-Hendy

2013

Biology of Reproduction

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Uterine fibroids (leiomyomas) are the most common benign tumors associated with excessive deposition of extracellular matrix (ECM)-associated proteins that increase fibroid tumorigenicity. Herein, we determined the expression levels of vitamin D receptor (VDR) protein in human uterine fibroids and compared these levels to those in adjacent normal myometrium. Using Western blot analysis, we found that more than 60% of uterine fibroids analyzed (25 of 40) expressed low levels of VDR. We also found that the biologically active 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), which functions via binding to its nuclear VDR, induced VDR in a concentration-dependent manner and reduced ECM-associated fibrotic and proteoglycans expression in immortalized human uterine fibroid cell line (HuLM). At 1-10 nM concentrations, 1,25(OH)2D3 significantly induced (P < 0.05) nuclear VDR, which was further stimulated by higher concentrations of 1,25(OH)2D3 in HuLM cells. 1,25(OH)2D3 at 10 nM also significantly reduced (P < 0.05) the protein expression of ECM-associated collagen type 1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) in HuLM cells. We also found that 1,25(OH)2D3 reduced mRNA and protein expressions of proteoglycans such as fibromodulin, biglycan, and versican in HuLM cells. Moreover, the aberrant expression of structural smooth muscle actin fibers was reduced by 1,25(OH)2D3 treatment in a concentration-dependent manner in HuLM cells. Taken together, our results suggest that human uterine fibroids express reduced levels of VDR compared to the adjacent normal myometrium and that treatment with 1,25(OH)2D3 can potentially reduce the aberrant expression of major ECM-associated proteins in HuLM cells. Thus, 1,25(OH)2D3 might be an effective, safe, nonsurgical treatment option for human uterine fibroids.

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“…In the latter disease, the ability of biglycan to engage TGF-β (Schaefer et al, 2005) could play a role in regulating the fibrotic response (Droguett et al, 2006). Notably, patients with rheumatoid arthritis (RA) show elevated levels of antibodies targeting biglycan in the affected synovial fluid (Polgar et al, 2003), and this process has been recently linked to fragmentation of collagen fibers, thus contributing to the RA phenotype (Antipova and Orgel, 2012). In a collagen-induced RA experimental model, fragmented biglycan was detected in serum (Genovese et al, 2013), implying that degraded biglycan from the ECM is antigenic and can produce autoantibodies that gradually causes damage.…”

Section: Soluble Biglycan: Ecm-derived Danger Signals In Non-kidnementioning

confidence: 99%

Soluble biglycan as a biomarker of inflammatory renal diseases

Hsieh

Nastase

Zeng-Brouwers

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small leucine-rich proteoglycan (SLRP) gene family. It is becoming increasingly evident that the matrix-unbound SLRPs strongly regulate the progression of inflammation and fibrosis. Soluble SLRPs are generated either via partial proteolytic processing of collagenous matrices or by de novo synthesis evoked by stress or injury. Liberated SLRPs can then bind to and activate Toll-like receptors, thus modulating downstream inflammatory signaling. Preclinical animal models and human studies have recently identified soluble biglycan as a key initiator and regulator of various inflammatory renal diseases. Biglycan, generated by activated macrophages, can enter the circulation and its elevated levels in plasma and renal parenchyma correlate with unfavorable renal function and outcome. In this review, we will focus on the critical role of soluble biglycan in inflammatory signaling in various renal disorders. Moreover, we will provide new data implicating proinflammatory effects of soluble decorin in unilateral ureteral obstruction. Finally, we will critically evaluate the potential application of soluble biglycan vis-à-vis other SLRPs (decorin, lumican and fibromodulin) as a promising target and novel biomarker of inflammatory renal diseases.

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Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglycan and decorin in patients with rheumatoid arthritis or other joint diseases

Abstract: These results indicate a significantly higher immunity to small proteoglycans in RA and seronegative spondylarthropathies than in OA suggesting a possible involvement in the pathogenesis of inflammatory rheumatic diseases.

Cited by 49 publications

References 25 publications

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

Non-Enzymatic Decomposition of Collagen Fibers by a Biglycan Antibody and a Plausible Mechanism for Rheumatoid Arthritis

1,25-Dihydroxyvitamin D3 Reduces Extracellular Matrix-Associated Protein Expression in Human Uterine Fibroid Cells1

Soluble biglycan as a biomarker of inflammatory renal diseases

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