title: Intranuclear Actin Regulates Osteogenesis.
abstract: Depolymerization of the actin cytoskeleton induces nuclear trafficking of regulatory proteins and global effects on gene transcription. We here show that in mesenchymal stem cells (MSCs), cytochalasin D treatment causes rapid cofilin-/importin-9-dependent transfer of G-actin into the nucleus. The continued presence of intranuclear actin, which forms rod-like structures that stain with phalloidin, is associated with induction of robust expression of the osteogenic genes osterix and osteocalcin in a Runx2-dependent manner, and leads to acquisition of osteogenic phenotype. Adipogenic differentiation also occurs, but to a lesser degree. Intranuclear actin leads to nuclear export of Yes-associated protein (YAP); maintenance of nuclear YAP inhibits Runx2 initiation of osteogenesis. Injection of cytochalasin into the tibial marrow space of live mice results in abundant bone formation within the space of 1 week. In sum, increased intranuclear actin forces MSC into osteogenic lineage through controlling Runx2 activity; this process may be useful for clinical objectives of forming bone.
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Buer
authors.initials: B
authors.lastname: Sen
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Gunes
authors.initials: G
authors.lastname: Uzer
authors.affiliation: Department of Physical Therapy, University of Indiana-Purdue, Indianapolis, Indiana.
authors.forename: William R
authors.initials: WR
authors.lastname: Thompson
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Styner
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Rubin
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D015638:Cytochalasin D / Q000008:administration & dosage; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000235:genetics*; D010590:Phalloidine / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D010590:Phalloidine; D015638:Cytochalasin D
keywords: Bone; Cofilin; Cytoskeleton; Importin 9; Mesenchymal stem cells; Runx2; Yes-associated protein