title: Targeted disruption of leucine-rich repeat kinase 1 but not leucine-rich repeat kinase 2 in mice causes severe osteopetrosis.
abstract: To assess the roles of Lrrk1 and Lrrk2, we examined skeletal phenotypes in Lrrk1 and Lrrk2 knockout (KO) mice. Lrrk1 KO mice exhibit severe osteopetrosis caused by dysfunction of multinucleated osteoclasts, reduced bone resorption in endocortical and trabecular regions, and increased bone mineralization. Lrrk1 KO mice have lifelong accumulation of bone and respond normally to the anabolic actions of teriparatide treatment, but are resistant to ovariectomy-induced bone boss. Precursors derived from Lrrk1 KO mice differentiate into multinucleated cells in response to macrophage colony-stimulating factor (M-CSF)/receptor activator of NF-κB ligand (RANKL) treatment, but these cells fail to form peripheral sealing zones and ruffled borders, and fail to resorb bone. The phosphorylation of cellular Rous sarcoma oncogene (c-Src) at Tyr-527 is significantly elevated whereas at Tyr-416 is decreased in Lrrk1-deficient osteoclasts. The defective osteoclast function is partially rescued by overexpression of the constitutively active form of Y527F c-Src. Immunoprecipitation assays in osteoclasts detected a physical interaction of Lrrk1 with C-terminal Src kinase (Csk). Lrrk2 KO mice do not show obvious bone phenotypes. Precursors derived from Lrrk2 KO mice differentiate into functional multinucleated osteoclasts. Our finding of osteopetrosis in Lrrk1 KO mice provides convincing evidence that Lrrk1 plays a critical role in negative regulation of bone mass in part through modulating the c-Src signaling pathway in mice.
authors.affiliation: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA.
authors.forename: Weirong
authors.initials: W
authors.lastname: Xing
authors.forename: Jeff
authors.initials: J
authors.lastname: Liu
authors.forename: Shaohong
authors.initials: S
authors.lastname: Cheng
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D005260:Female; D018390:Gene Targeting; D007527:Isoenzymes / Q000097:blood; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D010012:Osteogenesis; D010022:Osteopetrosis / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000097:blood; D010641:Phenotype; D010766:Phosphorylation; D011347:Procollagen / Q000097:blood; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D050505:Mutant Proteins; D010446:Peptide Fragments; D011347:Procollagen; C047202:procollagen Type I N-terminal peptide; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C585046:Lrrk1 protein, mouse; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: BONE DENSITY; BONE RESORPTION; CSK; KNOCKOUT; OSTEOCLAST; PIT FORMATION; c-SRC