title: Role of CrkII Signaling in RANKL-Induced Osteoclast Differentiation and Function.
abstract: Rac1, a member of small GTPases, is a key regulator of osteoclast differentiation and function. The Crk family adaptor proteins, consisting of Src homology (SH) 2 and SH3 protein-binding domains, regulate cell proliferation, migration, and invasion through Rac1 activation. In this study, we examined the role of CrkII in osteoclast differentiation and function. Retroviral overexpression of CrkII in osteoclast precursors enhanced osteoclast differentiation and resorptive function through Rac1 activation. The knockdown of CrkII in osteoclast precursors using small interfering RNA inhibited osteoclast differentiation and its resorption activity. Unlike wild-type CrkII, overexpression of the three SH domains in mutant forms of CrkII did not enhance either osteoclast differentiation or function. Phosphorylation of p130 Crk-associated substrate (p130Cas) by osteoclastogenic cytokines in preosteoclasts increased the interaction between p130Cas and CrkII, which is known to be involved in Rac1 activation. Furthermore, transgenic mice overexpressing CrkII under control of a tartrate-resistant acid phosphatase promoter exhibited a low bone mass phenotype, associated with increased resorptive function of osteoclasts in vivo. Taken together, our data suggest that the p130Cas/CrkII/Rac1 signaling pathway plays an important role in osteoclast differentiation and function, both in vitro and in vivo.
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea;
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea;
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea;
authors.forename: Inyoung
authors.initials: I
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea;
authors.forename: Semun
authors.initials: S
authors.lastname: Seong
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea; and.
authors.forename: Kwang-Il
authors.identifier: http://orcid.org/0000-0001-5380-6815
authors.initials: KI
authors.lastname: Nam
authors.affiliation: Department of Oral Microbiology and Immunology, Wonkwang University School of Dentistry, Iksan 570-749, Republic of Korea.
authors.forename: Seoung Hoon
authors.identifier: http://orcid.org/0000-0002-3488-8189
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea;
authors.forename: Kyung Keun
authors.identifier: http://orcid.org/0000-0002-7346-9526
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea; nacksung@jnu.ac.kr.
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D055114:X-Ray Microtomography
chemical_list: D050719:Crk-Associated Substrate Protein; D050737:Proto-Oncogene Proteins c-crk; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse