Abstract
Reducing the time required for initial integration of bone-contacting implants with host tissues would be of great clinical significance. Changes in osteoblast adhesion formation and reorganization of the F-actin cytoskeleton in response to altered topography are known to be upstream of osteoblast differentiation, and these processes are regulated by the Rho GTPases. Rac and RhoA (through Rho Kinase (ROCK)). Using pharmacological inhibitors, we tested how inhibition of Rac and ROCK influenced osteoblast adhesion, differentiation and mineralization on PT (Pre-treated) and SLA (sandblasted large grit, acid etched) topographies. Inhibition of ROCK, but not Rac, significantly reduced adhesion number and size on PT, with adhesion size consistent with focal complexes. After 1 day, ROCK, but not Rac inhibition increased osteocalcin mRNA levels on SLA and PT, with levels further increasing at 7 days post seeding. ROCK inhibition also significantly increased bone sialoprotein expression at 7 days, but not BMP-2 levels. Rac inhibition significantly reduced BMP-2 mRNA levels. ROCK inhibition increased nuclear translocation of Runx2 independent of surface roughness. Mineralization of osteoblast cultures was greater on SLA than on PT, but was increased by ROCK inhibition and attenuated by Rac inhibition on both topographies. In conclusion, inhibition of ROCK signalling significantly increases osteoblast differentiation and biomineralization in a topographic dependent manner, and its pharmacological inhibition could represent a new therapeutic to speed bone formation around implanted metals and in regenerative medicine applications.
Highlights
Titanium and its alloys have been used for bone-contacting implants for several decades due to their high biocompatibility, favourable mechanical properties and low corrosion [1,2]
We hypothesized that Rac and Rho-associated kinase (ROCK) pathways will play a role in the regulation of osteoblast adhesion, differentiation and biomineralization
The most prominent finding from our study is that inhibition of ROCK signaling in osteoblasts significantly increases osteocalcin (PT and SLA) and bone sialoprotein (SLA) expression at 1 week, and biomineralization at 4 weeks
Summary
Titanium and its alloys have been used for bone-contacting implants for several decades due to their high biocompatibility, favourable mechanical properties and low corrosion [1,2]. Many different topographies are found commercially on dental implants, but moderately roughened topographies, produced through additive techniques such as titanium plasma spraying or subtractive techniques such as grit-blasting, acid etching or anodization are most common [2,6]. Combinations of these treatments can be used, as in the case of the Sand-blasted, Large grit, and Acid etched (SLA) topography produced by grit blasting followed by acid etching (Junker et al, 2009; Zhao et al, 2005). The SLA topography has been shown to be osteoconductive in vitro [8,9,10,11,12], in vivo [13,14], as well as in the clinical setting, with implant viability of 96.7% [15] and 99% [16] reported at 5 years
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