Abstract
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.
Highlights
Mechanical stress has been long recognized to be an important regulatory factor in bone homeostasis and a determinant of skeletal morphology during development and in postnatal life [1]
Cbfa1 binds to the osteoblast-specific cis-acting element 2 (OSE2)1 [3], which is found in the promoter regions of all the major osteoblast-specific genes and controls their expression [2, 4, 5]
Mechanical Stretch Induces Cbfa1 Expression in human periodontal ligament (hPDL) Osteoblastic Cells—It is well established that hPDL cells bear an osteoblastic potential (20 –22)
Summary
Mechanical stress has been long recognized to be an important regulatory factor in bone homeostasis and a determinant of skeletal morphology during development and in postnatal life [1]. We demonstrate that low level mechanical deformation (stretching) of human osteoblastic cells directly up-regulates the expression and DNA binding activity of Cbfa1.
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