title: Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2.
abstract: Cytoskeletal changes in osteoclasts such as formation of actin ring is required for bone-resorbing activity. The tyrosine kinase Src is a key player in massive cytoskeletal change of osteoclasts, thereby in bone destruction. In order for Src to be activated, trafficking to the inner plasma membrane via myristoylation is of importance. A previous study reported that myristoleic acid derived from myristic acid, inhibited N-myristoyl-transferase, an essential enzyme for myristoylation process. This prompted us to investigate whether myristoleic acid could affect osteoclastogenesis. Indeed, we observed that myristoleic acid inhibited RANKL-induced osteoclast formation in vitro, especially, at later stages of differentiation. Myristoleic acid attenuated the tyrosine phosphorylation of c-Src and Pyk2, which associates with Src, by RANKL. When myristoleic acid was co-administered with soluble RANKL into mice, RANKL-induced bone loss was substantially prevented. Bone dissection clearly revealed that the number of multinucleated osteoclasts was significantly diminished by myristoleic acid. On the other hand, myristoleic acid treatment had little or no influence on early osteoclast differentiation markers, such as c-Fos and NFATc1, and proteins related to cytoskeletal rearrangement, including DC-STAMP, integrin αv and integrin β3 in vitro. Taken together, our data suggest that myristoleic acid is capable of blocking the formation of large multinucleated osteoclasts and bone resorption likely through suppressing activation of Src and Pyk2.
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors.forename: Jun-Oh
authors.initials: JO
authors.lastname: Kwon
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors.forename: Won Jong
authors.initials: WJ
authors.lastname: Jin
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors.forename: Bongjun
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea. Electronic address: hhbkim@snu.ac.kr.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea. Electronic address: zang1959@snu.ac.kr.
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D053245:RANK Ligand; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; C054211:9-tetradecenoic acid
keywords: Myristoleic acid; Myristoylation; Osteoclast; Pyk2; Src