Role and mechanism of action of leucine-rich repeat kinase 1 in bone

Abstract

Leucine-rich repeat kinase 1 (LRRK1) plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrk1 in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review summarizes recent advances on the functions of the Lrrk1-related family members, Lrrk1 deficiency-induced skeletal phenotypes, LRRK1 structure–function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.

Bone resorption: Enzyme regulates cells responsible for bone breakdown

An enzyme called LRRK1 plays a critical role in regulating bone resorption and provides an attractive drug target for treating bone diseases. In a review article, Weirong Xing and colleagues from the Jerry L. Pettis Memorial VA Medical Center in Loma Linda, California, USA, describe how researchers identified LRRK1 (leucine-rich repeat kinase 1) in a screen of genes involved in skeletal development. The authors summarize recent discoveries on the functions of LRRK1 and related proteins, including the mechanisms by which LRRK1 modulates the activity of bone-absorbing osteoclast cells. They explain how mice that lack the gene encoding LRRK1 develop a severe bone disease known as osteopetrosis in which bones harden and become denser as a consequence of osteoclast dysfunction. Drugs that target LRRK1 activity could have therapeutic value in people with weakened bones.

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