title: Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors.
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.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5089, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Vérollet
authors.forename: Anne
authors.initials: A
authors.lastname: Gallois
authors.forename: Romain
authors.initials: R
authors.lastname: Dacquin
authors.forename: Claire
authors.initials: C
authors.lastname: Lastrucci
authors.forename: Subramanya N M
authors.initials: SN
authors.lastname: Pandruvada
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ortega
authors.forename: Renaud
authors.initials: R
authors.lastname: Poincloux
authors.forename: Annie
authors.initials: A
authors.lastname: Behar
authors.forename: Céline
authors.initials: C
authors.lastname: Cougoule
authors.forename: Clifford
authors.initials: C
authors.lastname: Lowell
authors.forename: Talal
authors.initials: T
authors.lastname: Al Saati
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; D019061:src-Family Kinases
keywords: Src tyrosine kinases; cell migration; osteopetrosis; podosomes