Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis

Bone remodeling is a delicate balancing act between the bone matrix synthesizing osteoblasts and bone resorbing osteoclasts. Active bone metastases typically subvert this process to generate lesions that are comprised of extensive areas of pathological osteogenesis and osteolysis. The resultant increase in bone matrix remodeling enhances cytokine/growth factor bioavailability thus creating a vicious cycle that stimulates tumor progression. Given the extent of matrix remodeling occurring in the tumor–bone microenvironment, the expression of matrix metalloproteinases (MMPs) would be expected, since collectively they have the ability to degrade all components of the extracellular matrix (ECM). However, in addition to being “matrix bulldozers”, MMPs control the bioavailability and bioactivity of factors such as RANKL and TGFβ that have been described as crucial for tumor–bone interaction, thus implicating MMPs as key regulators of the vicious cycle of bone metastases.