title: Compressive force-produced CCN2 induces osteocyte apoptosis through ERK1/2 pathway.
abstract: Osteocytes produce various factors that mediate the onset of bone formation and resorption and play roles in maintaining bone homeostasis and remodeling in response to mechanical stimuli. One such factor, CCN2, is thought to play a significant role in osteocyte responses to mechanical stimuli, but its function in osteocytes is not well understood. Here, we showed that CCN2 induces apoptosis in osteocytes under compressive force loading. Compressive force increased CCN2 gene expression and production, and induced apoptosis in osteocytes. Application of exogenous CCN2 protein induced apoptosis, and a neutralizing CCN2 antibody blocked loading-induced apoptosis. We further examined how CCN2 induces loaded osteocyte apoptosis. In loaded osteocytes, extracellular signal-regulated kinase 1/2 (ERK1/2) was activated, and an ERK1/2 inhibitor blocked loading-induced apoptosis. Furthermore, application of exogenous CCN2 protein caused ERK1/2 activation, and the neutralizing CCN2 antibody inhibited loading-induced ERK1/2 activation. Therefore, this study demonstrated for the first time to our knowledge that enhanced production of CCN2 in osteocytes under compressive force loading induces apoptosis through activation of ERK1/2 pathway.
authors.affiliation: Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hoshi
authors.forename: Harumi
authors.initials: H
authors.lastname: Kawaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takahashi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takeshita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Seiryu
authors.forename: Sakhr A
authors.initials: SA
authors.lastname: Murshid
authors.forename: Taisuke
authors.initials: T
authors.lastname: Masuda
authors.forename: Takahisa
authors.initials: T
authors.lastname: Anada
authors.forename: Ryushi
authors.initials: R
authors.lastname: Kato
authors.forename: Hideki
authors.initials: H
authors.lastname: Kitaura
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Teruko
authors.initials: T
authors.lastname: Takano-Yamamoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002642:Chick Embryo; D019245:Compressive Strength; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: C526318:CCN2 protein, mouse; D055513:Connective Tissue Growth Factor; D048052:Mitogen-Activated Protein Kinase 3
keywords: APOPTOSIS; CCN2; ERK1/2; MECHANICAL STRESS; OSTEOCYTE