Protein production by osteoblasts: modulation by breast cancer cell-derived factors

Breast cancer cells (BCC) frequently metastasize to bone where they may cau se tumor-induced osteolysis (TIO). While the important eroding role of the osteoclasts in TIO is well admitted, the possibility that BCC and/or osteob lasts activated by tumoral factors could also directly degrade bone matrix in this pathology has been much less investigated. We show here that the ne t collagen amount produced in vitro by normal human osteoblasts and osteobl ast-like cells was significantly reduced by culture medium conditioned by s everal BCC lines, including three newly isolated ones. There was no evidenc e for a decrease in collagen synthesis, as assessed by the production of th e carboxyterminal propeptide of type I collagen. In contrast, the effect of BCC-derived medium on collagen amount was attenuated by inhibitors of matr ix metalloproteinases (MMPs) as well as by tranexamic acid, an inhibitor of the plasminogen conversion to plasmin, while it was abolished in presence of the two kinds of proteinase inhibitors. This osteoblastic protein degrad ation activity appeared to be attributable to factors secreted by the osteo blasts as well as by BCC. These factors had molecular weights lower as well as higher than 10 kD. Our data suggest that besides the eroding action of osteoclasts, BCC- and osteoblast-derived MMPs and serine proteinases might play a direct role in bone collagen degradation in TIO.