ABSTRACT In osteoclasts, Src controls podosome organization and bone degradation, which leads to an osteopetrotic phenotype in src ؊/؊ mice. Since this phenotype was even more severe in src ؊/؊ hck ؊/؊ mice, we examined the individual contribution of Hck in bone homeostasis. Compared to wt mice, hck ؊/؊ mice exhibited an osteopetrotic phenotype characterized by an increased density of trabecular bone and decreased bone degradation, although osteoclastogenesis was not impaired. Podosome organization and matrix degradation were found to be defective in hck ؊/؊ osteoclast precursors (preosteoclast) but were normal in mature hck ؊/؊ osteoclasts, probably through compensation by Src, which was specifically overexpressed in mature osteoclasts. As a consequence of podosome defects, the 3-dimensional migration of hck ؊/؊ preosteoclasts was strongly affected in vitro. In vivo, this translated by altered bone homing of preosteoclasts in hck ؊/؊ mice: in metatarsals of 1-wk-old mice, when bone formation strongly depends on the recruitment of these cells, reduced numbers of osteoclasts and abnormal developing trabecular bone were observed. This phenotype was still detectable in adults. In summmary, Hck is one of the very few effectors of preosteoclast recruitment described to date and thereby plays a critical role in bone remodeling.-Vérollet, C., Gallois, A., Dacquin, R., Lastrucci, C., Pandruvada, S. M. N., Ortega, N., Poincloux, R., Behar, A., Cougoule, C., Lowell, C., Al Saati, T., Jurdic, P., Maridonneau-Parini, I. Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors. FASEB J. 27, 3608 -3618 (2013). www.fasebj.org Key Words: osteopetrosis ⅐ cell migration ⅐ podosomes ⅐ Src tyrosine kinases Bone is renewed continuously by a process known as bone remodeling. Bone remodeling is accomplished by 3 cell types: osteocytes, osteoblasts, and osteoclasts (OCs). Osteocytes are the mechanical sensors of bone that regulate osteoclast formation. Osteoblasts synthetize the matrix and promote its mineralization, while OCs are responsible for degradation of bones during bone development, homeostasis, and repair. The formation and degradation of bone are tightly balanced in both time and space. A dysregulation of this tight balance between bone formation and bone degradation may result either in loss of bone mass, such as in osteoporosis, or in contrast, in a progressive increase in bone mass, such as in osteopetrosis. Degrading OCs are large multinucleated giant cells formed by the differentiation and fusion of mononuclear monocyte lineage precursors after stimulation by receptor activator of nuclear factor -B ligand (RANKL) and macrophage colony-stimulationg factor (M-CSF) (1-3). They are characterized by high levels of cathepsin K and tartrate resistant acidic phosphatase (TRAP) activities, whic
