MMP-13 is over-expressed in renal cell carcinoma bone metastasis and is induced by TGF-β1

Bone metastasis occurs frequently in renal cell carcinoma (RCC) patients causing significant morbidity by stimulating excessive osteolysis, yet the mechanisms responsible have been little studied. Matrix metalloproteinases (MMPs) are over-expressed in many cancer types and are believed to play a role in bone metastasis, however, the expression of MMPs in RCC bone metastasis (RBM) has not been investigated. Due to their ability to degrade the main component of organic bone matrix, type I collagen, we investigated the expression of MMP-1, -2, -8, -9, and -13 in RBM. By quantitative (q)RT-PCR, expression of MMP-13 was significantly increased in RBM tissues relative to that in RCC and adjacent normal kidney while no differences in the expression of MMP-1, -2, -8, or -9 mRNA were observed. Correspondingly, increased expression of MMP-13 protein was also observed in RBM relative to RCC by immunohistochemical analysis. Intriguingly, the expression of MMP-13 in the human RBM cell line RBM1-IT4 was stimulated by TGF-beta 1, a growth factor abundant in the bone microenvironment and known to promote RBM-induced osteolysis in animals. Exposure of RBM1-IT4 cells to TGF-beta 1 increased MMP-13 mRNA levels as well as the latent and active forms of MMP-13 protein. Further, stable expression of a dominant-negative TGF-beta type II receptor in RBM1-IT4 cells inhibited MMP-13 expression following TGF-beta 1 exposure. These data suggest that MMP-13 expression is elevated in RBM relative to primary RCC and adjacent normal kidney, and is regulated at the cellular level by TGF-beta 1.