Targeted disruption of leucine‐rich repeat kinase 1 but not leucine‐rich repeat kinase 2 in mice causes severe osteopetrosis

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.