Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis

Abstract

IntroductionA protein analysis using a mass spectrometry indicated that there are serum proteins showing significant quantitative changes after the administration of infliximab. Among them, connective tissue growth factor (CTGF) seems to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, this study was conducted to investigate how CTGF is associated with the disease progression of RA.MethodsSerum samples were collected from RA patients in active or inactive disease stages, and before or after treatments with infliximab. CTGF production was evaluated by ELISA, RT-PCR, indirect immunofluorescence microscopy, and immunoblotting. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, a bone resorption assay and osteoclasts specific catalytic enzymes productions.ResultsThe serum concentrations of CTGF in RA were greater than in normal healthy controls and disease controls. Interestingly, those were significantly higher in active RA patients compared to inactive RA patients. Furthermore, the CTGF levels significantly were decreased by infliximab concomitant with the disease amelioration. In addition, tumour necrosis factor (TNF)α can induce the CTGF production from synovial fibroblasts even though TNFα can oppositely inhibit the production of CTGF from chondrocytes. CTGF promoted the induction of the quantitative and qualitative activities of osteoclasts in combination with M-CSF and receptor activator of NF-κB ligand (RANKL). In addition, we newly found integrin αVβ3 on the osteoclasts as a CTGF receptor.ConclusionsThese results indicate that aberrant CTGF production induced by TNFα plays a central role for the abnormal osteoclastic activation in RA patients. Restoration of aberrant CTGF production may contribute to the inhibition of articular destruction in infliximab treatment.

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…Of the nine genes Articles in our group that met the more stringent false discovery rate, interestingly ZC3H12B encodes a protein with a role in proinflammatory actions of macrophages (31). In addition, connective tissue growth factor (CTGF) is associated with several functions including fibrosis, angiogenesis, and tumorigenesis and is believed to play a role in inflammatory disorders including rheumatoid arthritis and CTGF polymorphisms are associated with systemic sclerosis (32)(33)(34). Limitations of the study include small sample size, lack of patients with periodic fever or malignancy, sampling bias, and lack of a replication cohort.…”

Inhibition of Connective Tissue Growth Factor Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

“…Manns and coworkers also showed that CTGF is up-regulated in an experimental animal model of RA and that treatment with thrombospondin 1-derived peptide is associated with the down-regulation of CTGF occurring simultaneously with the amelioration of the disease (19). We have previously shown that CTGF enhances osteoclastogenesis in patients with RA and plays an important role in the pathogenesis of RA (6). Osteoclasts are commonly found within the erosive pit at the interface between the synovial inflammatory tissue and subchondral bone (20).…”

Hypoxia-Mediated Metastasis

“…Several known hypoxia-regulated proteins have been shown to drive osteolytic bone metastases. Connective tissue growth factor (Higgins et al 2004 ) is involved in osteoclastogenesis and bone resorption, liberating tumorpromoting factors from the bone matrix (Kang et al 2003 ;Nozawa et al 2009 ). These tumor-promoting factors include bone morphogenic proteins and transforming growth factor-β, which also are upregulated by hypoxia signaling (Falanga et al 1991 ;Maegdefrau et al 2009 ).…”