Ponticos, M. et al. Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum. 60, 2142–2155 (2009).

New research suggests that connective tissue growth factor (CTGF, also known as CCN2) is an essential component in the development of pulmonary fibrosis, a common clinical manifestation of systemic sclerosis. CTGF is a member of the matricellular class of proteins, and is involved in cell–matrix interactions during wound healing and connective tissue repair. Observations of elevated CTGF expression in the fibrotic lesions of patients with connective tissue diseases, however, suggest that the protein could also be a direct profibrotic mediator. “CTGF has previously been implicated in the promotion of liver fibrosis and diabetic nephropathy,” explains Andrew Leask, an investigator on the new study. “We wanted to see if CTGF is also important for lung fibrosis.”

The researchers used a well described model of bleomycin-induced lung injury in transgenic mice to explore the effects of CTGF on collagen expression and on the promoter region of the gene encoding collagen type 1 (Col1a2). Following intrathecal administration of belomycin or saline, they observed increased CTGF and collagen levels as well as elevated Col1a2 promoter activity in the lungs of fibrotic mice compared with controls, both in vivo and in vitro. Moreover, increased CTGF levels clearly preceded the accumulation of collagen in vivo, suggesting that CTGF-induced Col1a2 transcription leads to enhanced expression and synthesis of collagen in this model of pulmonary fibrosis.

Having identified a possible direct role for CTGF in the profibrotic response to lung injury, the researchers then sought to determine whether CTGF blockade could improve aspects of bleomycin-induced lung fibrosis. Compared with control treatment, mouse-specific CTGF small interfering RNA or anti-CTGF antibody (pIgY3) reduced both CTGF levels and Col1a2 promoter activity in the fibroblasts of bleomycin-challenged mice. Furthermore, administration of anti-CTGF in vivo resulted in reduced expression of type 1 collagen and α-smooth-muscle actin as well as improvements in tissue architecture, compared with control treatment.

The investigators went on to show that, unlike the production of collagen type 1 by transforming growth factor β, the actions of CTGF on Col1a2 transcription are SMAD-independent. Instead, they rely on the actions of the extracellular signal-regulated kinases 1 and 2 and C-Jun N-terminal mitogen-activated protein kinase signaling pathways.

Leask and colleagues believe that CTGF antagonism might be an avenue worth exploring for the future therapy of systemic sclerosis. “It is important to further elucidate the actions of CTGF on cells to generate methods of blocking the specific effects of CTGF,” says Leask. “These strategies could ultimately be used to generate specific drugs that block CTGF action in patients susceptible to fibrosis.”