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Departments of 1 Physiology and Biophysics, 2 Anatomy, and 3 Orthopaedic Surgery and 4 Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana 46202
Mechanical stimulation of bone induces new bone formation in
vivo and increases the metabolic activity and gene expression of
osteoblasts in culture. We investigated the role of the actin cytoskeleton and actin-membrane interactions in the transmission of
mechanical signals leading to altered gene expression in cultured MC3T3-E1 osteoblasts. Application of fluid shear to osteoblasts caused
reorganization of actin filaments into contractile stress fibers and
involved recruitment of
1-integrins and 
-actinin to
focal adhesions. Fluid shear also increased expression of two proteins
linked to mechanotransduction in vivo, cyclooxygenase-2 (COX-2) and the
early response gene product c-fos. Inhibition of actin stress fiber
development by treatment of cells with cytochalasin D, by expression of
a dominant negative form of the small GTPase Rho, or by microinjection
into cells of a proteolytic fragment of -actinin that inhibits
-actinin-mediated anchoring of actin filaments to integrins at the
plasma membrane each blocked fluid-shear-induced gene expression in
osteoblasts. We conclude that fluid shear-induced mechanical signaling
in osteoblasts leads to increased expression of COX-2 and c-Fos through
a mechanism that involves reorganization of the actin cytoskeleton.
Thus Rho-mediated stress fiber formation and the -actinin-dependent
anchorage of stress fibers to integrins in focal adhesions may promote
fluid shear-induced metabolic changes in bone cells.
mechanotransduction; -actinin; gene expression
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