IBMS BoneKEy | Perspective

The role of proteolytic enzymes in metastatic bone disease

R Daniel Bonfil
Michael L Cher



The interaction of cancer cells and the bone microenvironment leads to an alteration of the delicate physiologic balance between bone formation and resorption. Among the factors distorted due to the dialogue between tumor cells and bone stroma are proteases, which are key regulators of bone remodeling and invasion of cancer cells. In addition to their classical degradative function on extracellular matrix (ECM), many proteases have been shown to have new substrates and roles that are, one way or another, involved in intraosseous growth of cancer cells and associated bone remodeling. Despite mounting evidence demonstrating the contribution of proteases to bone metastasis and promising preclinical data with different protease inhibitors, disappointing results in clinical trials performed in cancer patients, generally with no skeletal metastatic disease, have discouraged further investigations. In this Perspective, we describe recent advances in understanding of the role of proteases in bone metastasis and discuss strategies that need to be considered in the development of new protease inhibitors and in the implementation of clinical trials.

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