title: Notch2 signaling promotes osteoclast resorption via activation of PYK2.
abstract: Notch signaling plays a central role in various cell fate decisions, including skeletal development. Recently, Notch signaling was implicated in osteoclast differentiation and maturation, including the resorption activity of osteoclasts. However, the specific involvement of notch signaling in resorption activity was not fully investigated. Here, we investigated the roles of Notch signaling in the resorption activity of osteoclasts by use of the gamma-secretase inhibitor dibenzazepine (DBZ). Attenuating Notch signaling by DBZ suppressed the expression of NFATc1, a master transcription factor for osteoclast differentiation. However, overexpression of a constitutively active form of NFATc1 did not fully rescue the effects of DBZ. DBZ suppressed the autophosphorylation of PYK2, which is essential for the formation of the podosome belt and sealing zone, with reduced c-Src/PYK2 interaction. We found that RANKL increases PYK2 activation accompanied by increased NICD2 production in osteoclasts. Overexpression of NICD2 in osteoclasts rescued DBZ-mediated suppression of resorption activity with promotion of PYK2 autophosphorylation and microtubule acetylation. Consistent with the in vitro results, DBZ strongly suppressed bone destruction in an interleukin-1-induced bone loss model. Collectively, these results demonstrate that Notch2 in osteoclasts plays a role in the control of resorption activity via the PYK2-c-Src-microtubule signaling pathway.
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.
authors.forename: Jung-Wook
authors.initials: JW
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.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Clinical Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea. Electronic address: hyunil74@kiom.re.kr.
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
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: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000494:pharmacology / Q000627:therapeutic use; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D008297:Male; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000072417:Protein Domains; D051883:Receptor, Notch2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D003984:Dibenzazepines; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine
keywords: Dibenzazepine; Dibenzazepine (PubChem CID: 11454028); Notch2; Osteoclast; PYK2; Resorption