The role of c-Src kinase in the regulation of osteoclast function.

The targeted disruption of c-Src impairs osteoclast bone resorbing activity, causing osteopetrosis. Although it has been reported that restoring only the c-Src adaptor function at least partly rescues the skeletal phenotypes, the importance of c-Src kinase activity remains controversial. We here highlight the contributions of the Src adaptor and kinase activities in cytoskeletal organization and osteoclast function using adenovirus vectors containing various mutants of Src or Pyk2. In addition, we describe the importance of c-Src in mitochondria, where it phosphorylates cytochrome c oxidase (Cox). Src-induced Cox activity is also required for bone resorbing activity of osteoclasts that require high levels of ATP. Thus, c-Src kinase activity not only on the plasma membrane but also within mitochondria is essential for the regulation of osteoclastic bone resorption.