title: Mitogen- and stress-activated protein kinase 1 activates osteoclastogenesis in vitro and affects bone destruction in vivo.
abstract: Mitogen- and stress-activated protein kinase (MSK) 1 is an important regulator of immune response and mitogenic signaling. In this study, we report for the first time that MSK1 was activated by the osteoclast differentiation factor receptor activator of nuclear factor kappa B ligand (RANKL) in osteoclast precursor cells. Inhibition of upstream kinases ERK1/2 and p38, but not JNK, suppressed MSK activation upon RANKL stimulation. An MSK1 inhibitor efficiently prevented the induction of c-Fos and NFATc1 and CREB phosphorylation by RANKL. Inhibition of MSK1 also successfully blocked RANKL-induced osteoclastogenesis. MSK knockdown with small interfering RNA significantly inhibited osteoclast differentiation and bone resorption. MSK1 did not affect osteoclast survival. The induction of c-Fos and NFATc1 and the phosphorylation of CREB and ATF2 were also inhibited by MSK1 knockdown. Moreover, knockdown of MSK1 significantly blocked recruitment of c-Fos to the NFATc1 promoter upon RANKL stimulation. Therefore, NFATc1-inducible osteoclast-specific genes were downregulated by MSK1 blockade. NFATc1 retrovirus transduction almost completely rescued the differentiation defect of MSK1-silenced cells. In vivo knockdown of MSK1 reduced RANKL-induced bone resorption as well as osteoclast formation. Thus, our results suggested that MSK1 is an important novel molecule involved in RANKL signaling and osteoclast differentiation.
authors.affiliation: Department of Cell and Developmental Biology, BK21 and DRI, Seoul National University, Seoul 110-749, Republic of Korea.
authors.forename: Jeongim
authors.initials: J
authors.lastname: Ha
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000378:metabolism*; D002454:Cell Differentiation; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000166:cytology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020928:Mitogen-Activated Protein Kinases