title: Mst2 Controls Bone Homeostasis by Regulating Osteoclast and Osteoblast Differentiation.
abstract: Mammalian sterile 20-like kinase 2 (Mst2) plays a central role in the Hippo pathway, controlling cell proliferation, differentiation, and apoptosis during development. However, the roles of Mst2 in osteoclast and osteoblast development are largely unknown. Here, we demonstrate that mice deficient in Mst2 exhibit osteoporotic phenotypes with increased numbers of osteoclasts and decreased numbers of osteoblasts as shown by micro-computed tomography (µCT) and histomorphometric analyses. Osteoclast precursors lacking Mst2 exhibit increased osteoclastogenesis and Nfatc1, Acp5, and Oscar expression in response to receptor activator of NF-κB ligand (RANKL) exposure. Conversely, Mst2 overexpression in osteoclast precursors leads to the inhibition of RANKL-induced osteoclast differentiation. Osteoblast precursors deficient in Mst2 exhibit attenuated osteoblast differentiation and function by downregulating the expression of Runx2, Alpl, Ibsp, and Bglap. Conversely, ectopic expression of Mst2 in osteoblast precursors increases osteoblastogenesis. Finally, we demonstrate that the NF-κB pathway is activated by Mst2 deficiency during osteoclast and osteoblast development. Our findings suggest that Mst2 is involved in bone homeostasis, functioning as a reciprocal regulator of osteoclast and osteoblast differentiation through the NF-κB pathway.
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Bang Ung
authors.initials: BU
authors.lastname: Youn
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, 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, Republic of Korea.
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Da-Hye
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Semun
authors.initials: S
authors.lastname: Seong
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Inyoung
authors.initials: I
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Che
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Yong-Wook
authors.initials: YW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D055114:X-Ray Microtomography; D000099317:Hippo Kinases
chemical_list: D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D053245:RANK Ligand; D000090742:Serine-Threonine Kinase 3; C505689:Tnfsf11 protein, mouse; C073701:Nfkb1 protein, mouse; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: BONE HOMEOSTASIS; MST2; NF-κB; OSTEOBLAST; OSTEOCLAST