Connective tissue growth factor stimulates osteosarcoma cell migration and induces osteosarcoma metastasis by upregulating VCAM-1 expression.

Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. However, the detailed mechanism associated with CTGF-directed migration in bone neoplasms is still mostly unknown. Through the in vivo and in vitro examination of osteosarcoma cells, this study suggests that VCAM-1 up-regulation and increased osteosarcoma cell migration are involved in this process. Antagonizing αvß3 integrin inhibited cell migration. Moreover, FAK, PI3K, Akt and NF-κB activation were also shown to be involved in CTGF-mediated osteosarcoma metastasis. Taken together, CTGF promotes VCAM-1 production and further induces osteosarcoma metastasis via the αvß3 integrin/FAK/PI3K/Akt/NF-κB signaling pathway, which could represent a promising clinical target to improve patient outcome.

TGF-Beta Blockade Increases Renal Inflammation Caused by the C-Terminal Module of the CCN2.

The CCN family member 2 (CCN2, also known as connective tissue growth factor) may behave as a risk biomarker and a potential therapeutic target for renal disease. CCN2 participates in the regulation of inflammation and fibrosis. TGF-ß is considered the main fibrogenic cytokine; however, in some pathological settings TGF-ß also has anti-inflammatory properties. CCN2 has been proposed as a downstream profibrotic mediator of TGF-ß, but data on TGF-ß role in CCN2 actions are scarce. Our aim was to evaluate the effect of TGF-ß blockade in CCN2-mediated experimental renal damage. Systemic administration of the C-terminal module of CCN2 to mice caused sustained renal inflammation. In these mice, TGF-ß blockade, using an anti-TGF-ß neutralizing antibody, significantly increased renal expression of the NGAL (a kidney injury biomarker), kidney infiltration by monocytes/macrophages, and upregulation of MCP-1 expression. The anti-inflammatory effect of TGF-ß seems to be mediated by a dysregulation of the systemic Treg immune response, shown by decreased levels of circulating CD4(+)/Foxp3(+)Treg cells. Our experimental data support the idea that TGF-ß exerts anti-inflammatory actions in the kidney and suggest that it is not an optimal therapeutic target.