Increased and correlated expression of connective tissue growth factor and transforming growth factor beta 1 in surgically removed periodontal tissues with chronic periodontitis.

Connective tissue growth factor (CTGF), also called CCN2, is a member of the CYR61, CTGF and NOV (CCN) family and plays an important role in cell proliferation, migration, angiogenesis, wound healing, and matrix production, and is critically involved in fibrotic diseases (1, 2). Studies have shown that the expression of CCN proteins including CTGF/CCN2 is increased in diseases related to chronic inflammation such as atherosclerosis, arthritis, cancers, and diabetic nephropathy and retinopathy (1). CTGF/CCN2 is produced by a variety of cells including monocytes, macrophages, fibroblasts, and epithelial cells and upregulated by transforming growth factor beta (TGFβ), inflammatory cytokines, high glucose and environment changes such as hypoxia and biomechanical stimuli (3). TGFβ and CTGF/CCN2 have pleiotrophic properties that play an important role in connective tissue homeostasis (3). It is well known that TGFβ and CTGF/CCN2 stimulate tissue remodeling and wound healing by increasing fibroblast proliferation, angiogenesis, and extracellular matrix (ECM) production (1). In addition, TGFβ is also a potent inhibitor of matrix metalloproteins (MMPs) and thus reduces collagen degradation (4). Paradoxically, studies have shown that TGFβ and CTGF/CCN2 also promote inflammation-associated tissue degradation. For example, Jagels et al. reported that TGFβ enhances production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and regulated upon activation, normal T cell expressed and secreted (RANTES) and thus increases recruitment of eosinophils, lympocytes and monocytes that are involved in chronic and allergic inflammation and tissue destruction (5). Nozawa et al. also reported that CTGF/CCN2 synergizes with macrophage colony-stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL) to enhance osteoclastogenesis and thus contributes to bone destruction in rheumatoid arthritis (6). Apparently, while TGFβ and CTGF/CCN2 primarily stimulate connective tissue production and promote fibrosis, they may have complex effects on both tissue regeneration and destruction in the setting of inflammation. Chronic periodontitis is triggered by Gram-negative bacteria and characterized by inflammatory tissue destruction of tooth-supporting structures of the periodontium. Interestingly, Lorencini et al. reported that gingival collagen fibers were reduced by 30%, but the fibers were thicker and more densely packed in rats with ligature-induced periodontitis when compared with rats without periodontitis, indicating that tissue inflammation and destruction are accompanied by tissue regeneration and remodeling in periodontitis (7). In consistence with this notion, studies have shown that periodontitis is associated with increased expression of TGFβ (8, 9), which may play a role in gingival tissue remodeling. However, the periodontal CTGF/CCN2 expression in patients with periodontitis remains unknown although it has been shown that CTGF/CCN2 is co-expressed with TGFβ in the gingival mucosa (10). In this study, we collected periodontal tissue specimens from 21 individuals with or without periodontitis at the time of indicated surgical procedures and quantified CTGF/CCN2 and TGFβ1 mRNA by real-time polymerase chain reaction (PCR). Results showed that the expression of both CTGF/CCN2 and TGFβ1 mRNA was significantly increased in patients with periodontitis.