The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells.
A primary goal of bone research is to understand the mechanism(s) by which mechanical forces dictate the cellular and metabolic activities of osteoblasts, the bone-forming cells. Several studies indicate that osteblastic cells respond to physical loading by transducing signals that alter gene expression patterns. Accumulated data have documented the fundamental role of the osteoblast-specific transcription factor Cbfa1 (core-binding factor) in osteoblast differentiation and function. Here, we demonstrate that low level mechanical deformation (stretching) of human osteoblastic cells directly up-regulates the expression and DNA binding activity of Cbfa1. This effect seems to be fine tuned by stretch-triggered induction of distinct mitogen-activated protein kinase cascades. Our novel finding that activated extracellular signal-regulated kinase mitogen-activated protein kinase physically interacts and phosphorylates endogenous Cbfa1 in vivo (ultimately potentiating this transcription factor) provides a molecular link between mechanostressing and stimulation of osteoblast differentiation. Elucidation of the specific modifiers and cofactors that operate in this mechanotranscription circuitry will contribute to a better understanding of mechanical load-induced bone formation which may set the basis for nonpharmacological intervention in bone loss pathologies.
Ziros
Panos G
PG
Department of Biochemistry, School of Medicine, University of Patras, Patras GR-26110, Greece.
Gil
Andrea-Paola Rojas
AP
Georgakopoulos
Tassos
T
Habeos
Ioannis
I
Kletsas
Dimitris
D
Basdra
Efthimia K
EK
Papavassiliou
Athanasios G
AG
D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D004247:DNA / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004247:DNA; D020928:Mitogen-Activated Protein Kinases